Heteroaryl urea neuropeptide Y Y5 receptor antagonists

ABSTRACT

The present invention relates to compounds represented by the structural Formula I:  
                 
or a pharmaceutically acceptable salt thereof, which are useful for the treatment of metabolic and eating disorders such as obesity and hyperphagia, and for the treatment of diabetes and associated disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. No. 10/177,345 filed onJun. 20, 2002, which is a Continuation-in-part of U.S. Ser. No.10/026,651 filed on Dec. 18, 2001, which claims the benefit of U.S.Provisional Application No. 60/257,308 filed on Dec. 18, 2000.

This invention relates to heteroaryl urea neuropeptide Y Y5 receptorantagonists useful in the treatment of eating disorders, pharmaceuticalcompositions containing the compounds, and methods of treatment usingthe compounds.

Neuropeptide Y (NPY) is a 36 amino acid neuropeptide that is widelydistributed in the central and peripheral nervous systems. NPY is amember of the pancreatic polypeptide family that also includes peptideYY and pancreatic polypeptide (Wahlestedt, C., and Reis, D., Ann. Rev.Toxicol., 32, 309, 1993). NPY elicits its physiological effects byactivation of at least six receptor subtypes designated Y1, Y2, Y3, Y4,Y5 and Y6 (Gehlert, D., Proc. Soc. Exp. Biol. Med., 218, 7, 1998;Michel, M. et al., Pharmacol. Rev., 50, 143, 1998). Centraladministration of NPY to animals causes dramatically increased foodintake and decreased energy expenditure (Stanley, B. and Leibowitz, S.,Proc. Natl. Acad. Sci. USA 82: 3940, 1985; Billington et al., Am J.Physiol., 260, R321, 1991). These effects are believed to be mediated atleast in part by activation of the NPY Y5 receptor subtype. Theisolation and characterization of the NPY Y5 receptor subtype has beenreported (Gerald, C. et al., Nature, 1996, 382, 168; Gerald, C. et al.WO 96/16542). Additionally, it has been reported that activation of theNPY Y5 receptor by administration of the Y5-selective agonist[D-Trp³²]NPY to rats stimulates feeding and decreases energy expenditure(Gerald, C. et al., Nature, 1996, 382, 168; Hwa, J. et al., Am. J.Physiol., 277 (46), R1428, 1999). Hence, compounds that block binding ofNPY to the NPY Y5 receptor subtype should have utility in the treatmentof eating disorders such as obesity, bulimia nervosa, anorexia nervosa,and in the treatment of disorders associated with obesity such as typeII diabetes, insulin resistance, hyperlipidemia, and hypertension.

Published PCT patent application WO 00/27845 describes a class ofcompounds, characterized therein as spiro-indolines, said to beselective neuropeptide Y Y5 receptor antagonists and useful for thetreatment of obesity and the complications associated therewith. Knownurea derivatives indicated as possessing therapeutic activity aredescribed in U.S. Pat. No. 4,623,662 (antiatherosclerotic agents) andU.S. Pat. No. 4,405,644 (treatment of lipometabolism).

Provisional application, U.S. Ser. No. 60/232,255 describes a class ofsubstituted urea neuropeptide Y Y5 receptor antagonists.

SUMMARY OF THE INVENTION

This invention relates to compounds of Formula I:

or a pharmaceutically acceptable salt and/or hydrate of said compound,

-   -   wherein    -   =A-B= is ═C(R⁴)—C(R⁵)═ and —X═Y— is —C(R⁶)═N—, —N═C(R⁷)—, —N═N—        or —S—, or    -   =A-B= is ═N—C(R⁵)═ and —X═Y— is —N═C(R⁷)—, —C(R⁶)═N—, —S— or        —O—, or    -   =A-B= is ═C(R⁴)—N═ and —X═Y— is —C(R⁶)═N—, —S— or —O—, or    -   =A-B= is ═N—N═ and —X═Y— is —S— or —O—, or    -   =A-B= is ═C(R⁴)— and —X═Y— is —S—N═, —N(R¹⁰)—N═, or    -   =A-B= is —C(R⁴)═ and —X═Y— is ═N—S—, or ═N—N(R¹⁰)—;    -   Z is    -   R¹ is H or —(C₁-C₆)alkyl;    -   R² is H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl or        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl;    -   Q is —OR¹³ or —NR¹³R¹⁴;    -   j is 1 or 2;    -   k is 0, 1 or 2;    -   l is 0, 1 or 2;    -   m is 0, 1 or 2;    -   n is 0 to 6;    -   p is 1, 2 or 3;    -   q is 1 or 2;    -   R⁴, R⁵, R⁶ and R⁷ may be the same or different, and are        independently selected from H, —OH, halogen, haloalkyl,        —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —CN, NR¹⁰R¹¹, NR¹³R¹⁴,        —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,        —O(C₁-C₆)alkyl(C₃-C₇)cycolalkyl, —S(C₁-C₆)alkyl,        —S(C₃-C₇)cycloalkyl and —S(C₁-C₆)alkyl(C₃-C₇)cycloalkyl;    -   R⁸ may be the same or different, and is independently selected        from H, halogen, —OH, haloalkyl, haloalkoxy, —CN, —NO₂,        —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, NR¹⁰R¹¹, NR¹³R¹⁴,        —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,        —O(C₁-C₆)alkyl(C₃-C₇)cycloalkyl and —CONR¹³R¹⁴;    -   R⁹ is —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl,        —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)haloalkyl,        —SO₂[hydroxy(C₂-C₆)alkyl], —SO₂[amino(C₂-C₆)alkyl],        —SO₂[alkoxy(C₂-C₆)alkyl], —SO₂[alkylamino(C₂-C₆)alkyl],        —SO₂[dialkylamino(C₂-C₆)alkyl], —SO₂(aryl), —SO₂(heteroaryl),        —SO₂[aryl(C₁-C₆) alkyl], —SO₂NR¹³R¹⁴, —CO(C₁-C₆)alkyl,        —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl,        CO(C₁-C₆)haloalkyl, —C(O)aryl, —C(O)heteroaryl, —CONR¹³R¹⁴,        —C(S)NR¹³R¹⁴, aryl, heteroaryl, —(CH₂)CONR¹³R¹⁴,        —C(═NCN)alkylthio, —C(═NCN)NR¹³R¹⁴, —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylaryl, —(C₁-C₆)alkylheteroaryl or —COOR¹²;    -   R¹⁰ is H or alkyl;    -   R¹¹ is H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, aryl, heteroaryl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl,        —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)haloalkyl,        —SO₂(aryl), —SO₂(heteroaryl), —CO(C₁-C₆)alkyl,        —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl,        —C(O)aryl, —C(O)heteroaryl, —CONR¹³R¹⁴ or —COOR¹²;    -   R¹² is —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylaryl,        —(C₁-C₆)alkylheteroaryl, aryl or heteroaryl;    -   R¹³ and R¹⁴ may be the same or different and are independently        H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylaryl, aryl or        heteroaryl; and,    -   R¹⁵ may be the same or different, and is H, —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, aryl,        heteroaryl, —CN, —CONR¹³R¹⁴, —COOR¹³, —OH, —O(C₁-C₆)alkyl,        —O(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —NR¹⁰R¹¹,        —NR¹³R¹⁴, or a —(C₁-C₆)alkyl group substituted by an aryl,        heteroaryl, hydroxy, alkoxy, —NR¹⁰R¹¹, —NR¹³R¹⁴, —CONR¹³R¹⁴, or        —COOR¹³ group.

The invention also relates to pharmaceutical compositions containing thecompounds of the invention, as well as methods of using the compoundsalone or in combination with other therapeutic agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of Formula I:

or a pharmaceutically acceptable salt and/or hydrate of said compound,or where applicable, a geometric or optical isomer or racemic mixturethereof,

-   -   wherein    -   =A-B= is ═C(R⁴)—C(R⁵)═ and —X═Y— is —C(R⁶)═N—, —N═C(R⁷)—, —N═N—        or —S—, or    -   =A-B= is ═N—C(R⁵)═ and —X═Y— is —N═C(R⁷)—, —C(R⁶)═N—, —S— or        —O—, or    -   =A-B= is ═C(R⁴)—N═ and —X═Y— is —C(R⁶)═N—, —S— or —O—, or    -   =A-B= is ═N—N═ and —X═Y— is —S— or —O—, or    -   =A-B= is ═C(R⁴)— and —X═Y— is —S—N═, —N(R¹⁰)—N═, or    -   =A-B= is —C(R⁴)═ and —X═Y— is ═N—S—, or ═N—N(R¹⁰)—;    -   Z is    -   R¹ is H or —(C₁-C₆)alkyl;    -   R² is H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl or        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl;    -   Q is —OR¹³, or —NR¹³R¹⁴;    -   j is 1 or 2;    -   k is 0, 1 or 2;    -   l is 0, 1 or 2;    -   m is 0, 1 or 2;    -   n is 0 to 6;    -   p is 1, 2 or 3;    -   q is 1 or 2;    -   R⁴, R⁵, R⁶ and R⁷ may be the same or different, and are        independently selected from H, —OH, halogen, haloalkyl,        —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —CN, NR¹⁰R¹¹,        NR¹³R¹⁴—O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,        —O(C₁-C₆)alkyl(C₃-C₇)cycolalkyl, —S(C₁-C₆)alkyl,        —S(C₃-C₇)cycloalkyl and —S(C₁-C₆)alkyl(C₃-C₇)cycloalkyl;    -   R⁸ may be the same or different, and is independently selected        from H, halogen, —OH, haloalkyl, haloalkoxy, —CN, —NO₂,        —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, NR¹⁰R¹¹, NR¹³R¹⁴,        —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,        —O(C₁-C₆)alkyl(C₃-C₇)cycloalkyl and —CONR¹³R¹⁴;    -   R⁹ is —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl,        —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)haloalkyl,        —SO₂[hydroxy(C₂-C₆)alkyl], —SO₂[amino(C₂-C₆)alkyl],        —SO₂[alkoxy(C₂-C₆)alkyl], —SO₂[alkylamino(C₂-C₆)alkyl],        —SO₂[dialkylamino(C₂-C₆)alkyl], —SO₂(aryl), —SO₂(heteroaryl),        —SO₂[aryl(C₁-C₆) alkyl], —SO₂NR¹³R¹⁴, —CO(C₁-C₆)alkyl,        —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl,        CO(C₁-C₆)haloalkyl, —C(O)aryl, —C(O)heteroaryl, —CONR¹³R¹⁴,        —C(S)NR¹³R¹⁴, aryl, heteroaryl, —(CH₂)CONR¹³R¹⁴,        —C(═NCN)alkylthio, —C(═NCN)NR¹³R¹⁴, —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkylaryl, —(C₁-C₆)alkylheteroaryl or —COOR¹²;    -   R¹⁰ is H or alkyl;    -   R¹¹ is H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, aryl, heteroaryl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl,        —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)haloalkyl,        —SO₂(aryl), —SO₂(heteroaryl), —CO(C₁-C₆)alkyl,        —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl,        —C(O)aryl, —C(O)heteroaryl, —CONR¹³R¹⁴ or —COOR¹²;    -   R¹² is —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylaryl,        —(C₁-C₆)alkylheteroaryl, aryl or heteroaryl;    -   R¹³ and R¹⁴ may be the same or different and are independently        H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,        —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylaryl, aryl or        heteroaryl; and,    -   R¹⁵ may be the same or different, and is H, —(C₁-C₆)alkyl,        —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, aryl,        heteroaryl, —CN, —CONR¹³R¹⁴, —COOR¹³, —OH, —O(C₁-C₆)alkyl,        —O(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —NR¹⁰R¹¹,        —NR¹³R¹⁴, or a —(C₁-C₆)alkyl group substituted by an aryl,        heteroaryl, hydroxy, alkoxy, —NR¹⁰R¹¹—NR¹³R¹⁴—CONR¹³R¹⁴ or        —COOR¹³ group.

Except where stated otherwise, the following definitions applythroughout the present specification and claims. These definitions applyregardless of whether a term is used by itself or in combination withother terms. Hence the definition of “alkyl” applies to “alkyl” as wellas to the “alkyl” portions of “alkoxy”, etc.

“Patient” includes both human and other mammals.

“Mammal” means humans and other animals, including companion and foodproducing animals.

“Alkyl” means an aliphatic hydrocarbon group, which may be straight orbranched and comprising 1 to 20 carbon atoms in the chain. Preferredalkyl groups contain 1 to 12 carbon atoms in the chain. More preferredalkyl groups contain 1 to 6 carbon atoms in the chain. Branched meansthat one or more lower alkyl groups such as methyl, ethyl or propyl, areattached to a linear alkyl chain.

“Lower alkyl” means a group having 1 to 6 carbon atoms in the chain,which may be straight or branched. The term “substituted alkyl” meansthat the alkyl group may be substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy,alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂, carboxy andalkylOC(O)—. Non-limiting examples of suitable alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising 2 to 15 carbon atoms in the chain. Preferred alkenyl groupshave 2 to 12 carbon atoms in the chain; and more preferably 2 to 6carbon atoms in the chain. Branched means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkenylchain. “Lower alkenyl” means 2 to 6 carbon atoms in the chain, which maybe straight or branched. The term “substituted alkenyl” means that thealkenyl group may be substituted by one or more substituents which maybe the same or different, each substituent being independently selectedfrom halo, alkyl, aryl, cycloalkyl, cyano, and alkoxy. Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, and 3-methylbut-2-enyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising 2 to 15 carbon atoms in the chain. Preferred alkynyl groupshave 2 to 12 carbon atoms in the chain; and more preferably 2 to 4carbon atoms in the chain. Branched means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkynylchain. “Lower alkynyl” means 2 to 6 carbon atoms in the chain, which maybe straight or branched. Non-limiting examples of suitable alkynylgroups include ethynyl, propynyl, and 2-butynyl. The term “substitutedalkynyl” means that the alkynyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from alkyl, aryl and cycloalkyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Thearyl group can be unsubstituted or optionally substituted on the ringwith one or more substituents which may be the same or different, eachbeing independently selected from alkyl, aryl, OCF₃, alkylOC(O)—,arylOC(O)—, CF₃, heteroaryl, aralkyl, alkylaryl, heteroaralkyl,alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl,aroyl, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, heterocyclyl, heterocyclenyl, Y₁Y₂N—,Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ may be thesame or different each being independently selected from hydrogen,alkyl, aryl, and aralkyl. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl. The “aryl” group can also be substituted bylinking two adjacent carbons on its aromatic ring via a combination ofone or more carbon atoms and one or more oxygen atoms such as, forexample, methylenedioxy, ethylenedioxy, and the like.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in whichone or more of the ring atoms is an element other than carbon, forexample nitrogen, oxygen or sulfur, alone or in combination. Preferredheteroaryls contain 5 to 6 ring atoms. The “heteroaryl” can beoptionally substituted on the ring by replacing an available hydrogen onthe ring by one or more substituents which may be the same or different,each being independently selected from alkyl, aryl, heteroaryl, aralkyl,alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-,Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y, and Y₂ may be the same ordifferent, each being independently selected from hydrogen, alkyl, aryl,and aralkyl. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl,triazolyl, and the like.

“Aralkyl” means an aryl-alkyl- group in which the aryl and alkyl are aspreviously described. Preferred aralkyls comprise a lower alkyl group.Non-limiting examples of suitable aralkyl groups include benzyl,2-phenylethyl and naphthlenylmethyl. The bond to the parent moiety isthrough the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting examples of suitable alkylaryl groups includebenzyl, o-tolyl, m-tolyl, p-tolyl and o-, p-, and m-xylyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms.Preferred cycloalkyl rings contain 5 to 7 ring atoms. The cycloalkyl canbe optionally substituted on the ring by replacing an available hydrogenon the ring by one or more substituents which may be the same ordifferent, each being independently selected from alkyl, aryl,heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl,alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, whereinY₁ and Y₂ may be the same or different each being independently selectedfrom hydrogen, alkyl, aryl, and aralkyl. Non-limiting examples ofsuitable monocyclic cycloalkyls include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examplesof suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl,adamantyl and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine or bromine, and more preferred are fluorine andchlorine.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above. Thepreferred halogen is fluoride. Specific examples, but non-limitingexamples include a halo(C₁-C₆)alkyl, —CF₂CH₃, —CH₂F₃ and —CF₃.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms whichcontains at least one carbon-carbon double bond. Preferred cycloalkenylrings contain 5 to 7 ring atoms. The cycloalkenyl can be optionallysubstituted on the ring by replacing an available hydrogen on the ringby one or more substituents which may be the same or different, eachbeing independently selected from alkyl, aryl, heteroaryl, aralkyl,alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-,Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or differenteach being independently selected from hydrogen, alkyl, aryl, andaralkyl. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, inwhich one or more of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur atom, alone or incombination, and which contains at least one carbon-carbon double bondor carbon-nitrogen double bond. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclenyl ringscontain 5 to 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted on the ring by replacing an availablehydrogen on the ring by one or more substituents which may be the sameor different, each being independently selected from alkyl, aryl,heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl,alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, whereinY₁ and Y₂ may be the same or different each being independently selectedfrom hydrogen, alkyl, aryl, and aralkyl. The nitrogen or sulfur atom ofthe heterocyclenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic azaheterocyclenyl groups include 1,2-dihydropyridyl,1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl and the like. Non-limitingexamples of suitable oxaheterocyclenyl groups include3,4-dihydro-2H-pyran, dihydrofuranyl, and the like. Non-limiting exampleof a suitable multicyclic oxaheterocyclenyl group is7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitablemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising 3 to 10 ring atoms, preferably 5 to 10 ringatoms, in which one or more of the atoms in the ring system is anelement other than carbon, for example nitrogen, oxygen or sulfur, aloneor in combination. There are no adjacent oxygen and/or sulfur atomspresent in the ring system. Preferred heterocyclyls contain 5 to 6 ringatoms. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom, respectively, ispresent as a ring atom. The heterocyclyl can be optionally substitutedon the ring by replacing an available hydrogen on the ring by one ormore substituents which may be the same or different, each beingindependently selected from alkyl, aryl, heteroaryl, aralkyl, alkylaryl,aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy,hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro,cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl,arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio,aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, whereinY₁ and Y₂ may be the same or different each being independently selectedfrom hydrogen, alkyl, aryl, and aralkyl. The nitrogen or sulfur atom ofthe heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic heterocyclyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl and the like.

“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkylas defined herein by removal of a hydrogen atom from the cycloalkylportion. Preferred arylcycloalkyls are those wherein aryl is phenyl andthe cycloalkyl consists of 5 to 6 ring atoms. The arylcycloalkyl can beoptionally substituted on the ring by replacing an available hydrogen onthe ring by one or more substituents which may be the same or different,each being independently selected from alkyl, aryl, heteroaryl, aralkyl,alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-,Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or differenteach being independently selected from hydrogen, alkyl, aryl, andaralkyl. Non-limiting examples of suitable arylcycloalkyls include1,2,3,4-tetrahydronaphthyl, and the like. The bond to the parent moietyis through a non-aromatic carbon atom.

“Cycloalkylaryl” means a group derived from a fused arylcycloalkyl asdefined herein by removal of a hydrogen atom from the aryl portion.Non-limiting examples of suitable cycloalkylaryls are as describedherein for an arylcycloalkyl group, except that the bond to the parentmoiety is through an aromatic carbon atom.

“Heteroarylcycloalkyl” means a group derived from a fused heteroaryl andcycloalkyl as defined herein by removal of a hydrogen atom from thecycloalkyl portion. Preferred heteroarylcycloalkyls are those whereinthe heteroaryl thereof consists of 5 to 6 ring atoms and the cycloalkylconsists of 5 to 6 ring atoms. The prefix aza, oxa or thia beforeheteroaryl means that at least a nitrogen, oxygen or sulfur atom ispresent respectively as a ring atom. The heteroarylcycloalkyl can beoptionally substituted on the ring by replacing an available hydrogen onthe ring by one or more substituents which may be the same or different,each being independently selected from alkyl, aryl, heteroaryl, aralkyl,alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio,heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl,cycloalkenyl, heterocyclyl, heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-,Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or differenteach being independently selected from hydrogen, alkyl, aryl, andaralkyl. The nitrogen atom of the heteroaryl portion of theheteroarylcycloalkyl can be optionally oxidized to the correspondingN-oxide. Non-limiting examples of suitable heteroarylcycloalkyls include5,6,7,8-tetrahydroquinolinyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, andthe like. The bond to the parent moiety is through a non-aromatic carbonatom.

“Cycloalkylheteroaryl” means a group derived from a fusedheteroarylcycloalkyl as defined herein by removal of a hydrogen atomfrom the heteroaryl portion. Non-limiting examples of suitablecycloalkylheteroaryls are as described herein for heteroarylcycloalkyl,except that the bond to the parent moiety is through an aromatic carbonatom.

“Aralkenyl” means an aryl-alkenyl- group in which the aryl and alkenylare as previously described. Preferred aralkenyls contain a loweralkenyl group. Non-limiting examples of suitable aralkenyl groupsinclude 2-phenethenyl and 2-naphthylethenyl. The bond to the parentmoiety is through the alkenyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. Thebond to the parent moiety is through the alkyl.

“Heteroaralkenyl” means an heteroaryl-alkenyl- group in which theheteroaryl and alkenyl are as previously described. Preferredheteroaralkenyls contain a lower alkenyl group. Non-limiting examples ofsuitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through thealkenyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, Alkynyl-C(O)—,cycloalkyl-C(O)—, cycloalkenyl-C(O)—, or cycloalkynyl-C(O)— group inwhich the various groups are as previously described. The bond to theparent moiety is through the carbonyl. Preferred acyls contain a loweralkyl. Non-limiting examples of suitable acyl groups include formyl,acetyl, propanoyl, 2-methylpropanoyl, and cyclohexanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1- and 2-naphthoyl. “Heteroaroyl” means a heteroaryl-C(O)— group inwhich the heteroaryl group is as previously described. Non-limitingexamples of suitable groups include nicotinoyl and pyrrol-2-ylcarbonyl.The bond to the parent moiety is through the carbonyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy and isopropoxy. The alkyl group islinked to an adjacent moiety through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” means an aralkyl-O— group in which the aralkyl groups is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Alkylamino” means an —NH₂ group in which one or more of the hydrogenatoms on the nitrogen is replaced by an alkyl group as defined above.Additionally, “dialkylamino” means an —NH₂ group where two of thehydrogen atoms on the nitrogen have been replaced by an alkyl group,preferably a lower alkyl group.

“Arylamino” means an —NH₂ group in which one or more of the hydrogenatoms on the nitrogen is replaced by an aryl group as defined above.

“Alkylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio, ethylthio, i-propylthio and heptylthio. The bond tothe parent moiety is through the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Alkoxycarbonyl” means an alkoxy group defined earlier linked to anadjacent moiety through a carbonyl. Non-limiting examples ofalkoxycarbonyl groups include —CH₃C(O)—, CH₃CH₂C(O)— and the like.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylheteroaryl” means an -alkyl-heteroaryl group in which the alkyland heteroaryl groups are previously described. The bond to the parentmoiety is through the alkyl.

“Alkylsulfonyl” means an alkyl-SO₂— group. Preferred groups are those inwhich the alkyl group is lower alkyl. The bond to the parent moiety isthrough the sulfonyl.

“Alkylsulfinyl” means an alkyl-S(O)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfinyl.

“Arylsulfonyl” means an aryl-SO₂— group. The bond to the parent moietyis through the sulfonyl.

“Arylsulfinyl” means an aryl-S(O)— group. The bond to the parent moietyis through the sulfinyl.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The term “mammal” as used herein, includes humans; companion animalssuch as dogs, cats, horses, monkeys and others; and food bearing animalssuch as cattle, cows, chickens and others.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

When a variable appears more than once in the structural formula, theidentify of each variable appearing more than once maybe independentlyselected form the definition for that variable.

N-oxides can form on a tertiary nitrogen present in an R substituent, oron ═N— in a heteroaryl ring substitutent and are included in thecompounds of formula I.

The term “chemically stable compound” is defined as a compound that canbe isolated, characterized, and tested for biological activity.

For compounds of the invention having at least one asymmetrical carbonatom, all isomers, including diastereomers, enantiomers and rotationalisomers are contemplated as being part of this invention. The inventionincludes d and l isomers in both pure form and in admixture, includingracemic mixtures. Isomers can be prepared using conventional techniques,either by separating isomers of a compound of formula I or bysynthesizing individual isomers of a compound of formula I.

Compounds of formula I can exist in unsolvated and solvated forms,including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for purposes of thisinvention.

A compound of formula I may form pharmaceutically acceptable salts withorganic and inorganic acids. Examples of suitable acids for saltformation are hydrochloric, sulfuric, phosphoric, acetic, citric,malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose skilled in the art. The salts are prepared by contacting the freebase forms with a sufficient amount of the desired acid to produce asalt in the conventional manner. The free base forms may be regeneratedby treating the salt with a suitable dilute aqueous base solution, suchas dilute aqueous sodium hydroxide, potassium carbonate, ammonia orsodium bicarbonate. The free base forms differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

In a preferred group of compounds of Formula I, the heterocyclic groupattached to

is

-   -   R¹⁵ is Hand R³ is    -   the sum of j and k is 2 or 3;    -   and the sum of l and m is 2 or 3.

In particular, the preferred group includes the above compounds whereinR¹ is hydrogen, R² is hydrogen or (C₁-C₆)alkyl, R⁴, R⁵, R⁶ and R⁷ arehydrogen or halogen, R⁸ is independently selected from H, halogen,—O(C₁-C₆)alkyl, —OH, haloalkyl and haloalkoxy, R⁹ is —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂aryl,—SO₂heteroaryl, —SO₂NR¹³R¹⁴, —CO(C₁-C₆)alkyl, —CO(C₃-C₇)cycloalkyl,—CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —C(O)aryl, —C(O)heteroaryl, aryl,heteroaryl, R¹⁰ is H or —(C₁-C₆)alkyl, R¹¹ is —SO₂(C₁-C₆)alkyl, Q is—OR¹³ or —NR¹³R¹⁴; R¹³ and R¹⁴ may be the same or different, and areindependently H or —(C₁-C₆)alkyl; the sum of j and k is 2 or 3; the sumof l and m is 2 or 3; and n is 0 to 6.

Another aspect of this invention is a method of treating a patienthaving a disease or condition mediated by NPY by administering atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt of said compound to the mammal. It ispreferred that the receptor is the NPY-5 receptor.

Another aspect of this invention is directed to a method of treatingobesity comprising administering to a patient in need of such treatmenta therapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to a method for treatingeating and metabolic disorders such as bulimia and anorexia comprisingadministering to a patient a therapeutically effective amount of acompound of Formula I or a pharmaceutically acceptable salt of saidcompound.

Another aspect of this invention is directed to a method for treatinghyperlipidemia comprising administering to a patient a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt of said compound.

Another aspect of this invention is directed to a method for treatingcellulite and fat accumulation comprising administering to a patient atherapeutically effective amount of a compound of Formula I or apharmaceutically acceptable salt of said compound.

Another aspect of this invention is directed to a method for treatingtype II diabetes comprising administering to a patient a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt of said compound.

In addition to the “direct” effect of the compounds of this invention onthe NPY5 subtype, there are diseases and conditions that will benefitfrom the weight loss such as insulin resistance, impaired glucosetolerance, Type II Diabetes, hypertension, hyperlipidemia,cardiovascular disease, gall stones, certain cancers, and sleep apnea.

The compounds of the invention may also have utility in the treatment ofcentral nervous system disorders such as seizures, depression, anxiety,alcoholism, pain; metabolic disorders such as hormone abnormalities;bone diseases such as osteoporosis, osteopenia, and Paget's disease;cardiovascular and renal disorders such hypertension, cardiachypertrophy, vasopspasm and nephropathy; sexual and reproductivedisorders; gastrointestinal disorders such as Crohn's disease; andrespiratory diseases such as asthma.

This invention is also directed to pharmaceutical compositions whichcomprise an amount of a compound of Formula I or a pharmaceuticallyacceptable salt of said compound and a pharmaceutically acceptablecarrier therefor.

This invention is also directed to pharmaceutical compositions for thetreatment of obesity which comprise an obesity treating amount of acompound of Formula, I r a pharmaceutically acceptable salt of saidcompound and a pharmaceutically acceptable carrier therefor.

Compounds of formula I may be produced by processes known to thoseskilled in the art as shown in the following reaction schemes and in thepreparations and examples below.

In Scheme 1, a nitro heteroaryl halide is coupled to an aryl boronicacid to give a nitro-substituted biaryl derivative. Reduction of thenitro group gives a biaryl amine derivative. Alternatively, an aminoheteroaryl halide derivative is coupled to an aryl boronic acidderivative to directly give an amino biaryl derivative. Treatment of thebiaryl amine with a reagent such as phenyl chloroformate, 4-nitrophenylchloroformate, triphosgene, or N,N′-disuccinimidyl carbonate and anorganic base, followed by an amino substituted cyclic amine derivativewith the ring nitrogen protected, gives a urea derivative (path A).Cleavage of the protecting group provides an amine that can bederivatized by treatment with, for example, acyl chlorides, sulfonylchlorides, and isocyanates. Alternatively, in the urea-forming step anamino substituted cyclic amine derivative wherein the ring nitrogen isderivatized with an R⁹ substituent can be used (path B). Path B is thepreferred method when R⁹ is aryl or heteroaryl. Compounds of Formula Iwhere

can be prepared by the methods outlined in Scheme 1.

In Scheme 2, a biaryl amine derivative is treated with triphosgene and abase followed by treatment with 4-(methylamino)cyclohexanone ethyleneketal to give a urea derivative. Deprotection of the ketal, for example,by treatment with a strong acid, gives a ketone derivative. The ketonecan then be derivatized by treatment with QNH₂.

In Scheme 3, an acid chloride is condensed with thiosemicarbazide togive an N-acyl thiosemicarbazide derivative. Treatment of the N-acylthiosemicarbazide with a strong acid results in the formation of anaminothiadiazole derivative. The aminothiadiazole is converted to asubstituted urea derivative as described earlier.

In Scheme 4 an alpha bromo acetal is condensed with thiourea to form a5-substituted 2-aminothiazole derivative. The 2-aminothiazole derivativeis converted to a substituted urea derivative as described in earlierschemes.

In Scheme 5, a 5-halo-2-nitrothiazole derivative is coupled to anarylzinc halide under palladium catalysis to give a2-aryl-5-nitrothiazole derivative. The 5-nitrothiazole derivative isthen converted to a substituted urea derivative as described in earlierSchemes.

The compounds of formula I exhibit selective neuropeptide Y Y5 receptorantagonizing activity, which has been correlated with pharmatcetucalactivity for treating eating disorders, such as obesity and hyperphagia,and diabetes.

The compounds of formula I display pharmacological activity in testprocedures designed to demonstrate neuropeptide Y Y5 receptor antagonistactivity. The compounds are non-toxic at pharmaceutically therapeuticdoses. Following are descriptions of the test procedures.

cAMP Assay

HEK-293 cells expressing the Y5 receptor subtype were maintained inDulbecco's modified Eagles' media (Gico-BRL) supplemented with 10% FCS(ICN), 1% penicillin-streptomycin and 200 μg/ml Geneticin© (GibcoBRL#11811-031) under a humidified 5% CO₂ atmosphere. Two days prior toassay, cells were released from T-175 tissue culture flasks using celldissociation solution (1×; non-enzymatic [Sigma #C-5914]) and seededinto 96-well, flat-bottom tissue culture plates at a density of 15,000to 20,000 cells per well. After approximately 48 hours, the cellmonolayers were rinsed with Hank's balanced salt solution (HBSS) thenpreincubated with approximately 150 μl/well of assay buffer (HBSSsupplemented with 4 mM MgCl₂, 10 mM HEPES, 0.2% BSA [HH]) containing 1mM 3-isobutyl-1-methylxanthine ([IBMX] Sigma #1-587) with or without theantagonist compound of interest at 37° C. After 20 minutes the 1 mMIBMX-HH assay buffer (+antagonist compound) was removed and replacedwith assay buffer containing 1.5 μM (CHO cells) or 5 μM (HEK-293 cells)forskolin (Sigma #F-6886) and various concentrations of NPY in thepresence or absence of one concentration of the antagonist compound ofinterest. At the end of 10 minutes, the media were removed and the cellmonolayers treated with 75 μl ethanol. The tissue culture plates wereagitated on a platform shaker for 15 minutes, after which the plateswere transferred to a warm bath in order to evaporate the ethanol. Uponbringing all wells to dryness, the cell residues were resolubilized with250 □l FlashPlate® assay buffer. The amount of cAMP in each well wasquantified using the [¹²⁵I]-cAMP FlashPlate® kit (NEN #SMP-001) andaccording to the protocol provided by the manufacturer. Data wereexpressed as either pmol cAMP/ml or as percent of control. All datapoints were determined in triplicate and EC₅₀'s (nM) were calculatedusing a nonlinear (sigmoidal) regression equation (GraphPad Prism™). TheK_(B) of the antagonist compound was estimated using the followingformula:K _(B) =[B]/(1−{[A′]/[A]})where

-   -   [A] is the EC₅₀ of the agonist (NPY) in the absence of        antagonist,    -   [A′] is the EC₅₀ of the agonist (NPY) in the presence of        antagonist,    -   and [B] is the concentration of the antagonist.        NPY Receptor Binding Assay

Human NPY Y5 receptors were expressed in CHO cells. Binding assays wereperformed in 50 mM HEPES, pH 7.2, 2.5 mM CaCl₂, 1 mM MgCl₂ and 0.1% BSAcontaining 5-10 μg of membrane protein and 0.1 nM ¹²⁵L-peptide YY in atotal volume of 200 μl. Non-specific binding was determined in thepresence of 1 μM NPY. The reaction mixtures were incubated for 90minutes at room temperature then filtered through Millipore MAFC glassfiber filter plates which had been pre-soaked in 0.5% polyethleneimine.The filters were washed with phosphate-buffered saline, andradioactivity was measured in a Packard TopCount scintillation counter.

For the compounds of this invention, a range of neuropeptide Y5 receptorbinding activity from about 0.2 nM to about 500 nM was observed.Compounds of this invention preferably have a binding activity in therange of about 0.2 nM to 250 nM, more preferably about 0.2 to 100 nM,and most preferably about 0.2 to 10 nM.

Yet another aspect of this invention are combinations of a compound ofFormula I or a pharmaceutically acceptable salt of said compound andother compounds as described below.

Accordingly, another aspect of this invention is a method for treatingobesity comprising administering to a mammal (e.g., a female or malehuman)

-   -   a. an amount of a first compound, said first compound being a        Formula I compound or a pharmaceutically acceptable salt of said        compound; and    -   b. an amount of a second compound, said second compound being an        anti-obesity and/or anorectic agent such as a B₃ agonist, a        thyromimetic agent, an anoretic agent, or an NPY antagonist        wherein the amounts of the first and second compounds result in        a therapeutic effect.

This invention is also directed to a pharmaceutical combinationcomposition comprising: a therapeutically effective amount of acomposition comprising

-   -   a first compound, said first compound being a Formula I compound        or a pharmaceutically acceptable salt of said compound    -   a second compound, said second compound being an anti-obesity        and/or anorectic agent such as a β₃ agonist, a thyromimetic        agent, an anoretic, or an NPY antagonist; and/or optionally a        pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a kit comprising:

-   -   a. an amount of a Formula I compound or a pharmaceutically        acceptable salt of said compound and a pharmaceutically        acceptable carrier, vehicle or diluent in a first unit dosage        form;    -   b. an amount of an anti-obesity and/or anorectic agent such as a        β₃ agonist, a thyromimetic agent, an anoretic agent, or an NPY        antagonist and a pharmaceutically acceptable carrier, vehicle or        diluent in a second unit dosage form; and    -   c. means for containing said first and second dosage forms        wherein the amounts of the first and second compounds result in        a therapeutic effect.

Preferred anti-obesity and/or anorectic agents (taken singly or in anycombination thereof) in the above combination methods, combinationcompositions and combination kits are:

-   -   phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a        cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a        monoamine reuptake inhibitor (such as sibutramine), a        sympathomimetic agent, a serotonergic agent (such as        dexfenfluramine or fenfluramine), a dopamine agonist (such as        bromocriptine), a melanocyte-stimulating hormone receptor        agonist or mimetic, a melanocyte-stimulating hormone analog, a        cannabinoid receptor antagonist, a melanin concentrating hormone        antagonist, the OB protein (hereinafter referred to as        “leptin”), a leptin analog, a leptin receptor agonist, a galanin        antagonist or a GI lipase inhibitor or decreaser (such as        orlistat). Other anorectic agents include bombesin agonists,        dehydroepiandrosterone or analogs thereof, glucocorticoid        receptor agonists and antagonists, orexin receptor antagonists,        urocortin binding protein antagonists, agonists of the        glucagon-like peptide-1 receptor such as Exendin and ciliary        neurotrophic factors such as Axokine.

Another aspect of this invention is a method treating diabetescomprising administering to a mammal (e.g., a female or male human)

-   -   a. an amount of a first compound, said first compound being a        Formula I compound or a pharmaceutically acceptable salt of said        compound; and    -   b. an amount of a second compound, said second compound being an        aldose reductase inhibitor, a glycogen phosphorylase inhibitor,        a sorbitol dehydrogenase inhibitor, a protein tyrosine        phosphatase 1B inhibitor, a dipeptidyl protease inhibitor,        insulin (including orally bioavailable insulin preparations), an        insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such        as troglitazone, rosaglitazone, pioglitazone or GW-1929, a        sulfonylurea, glipazide, glyburide, or chlorpropamide wherein        the amounts of the first and second compounds result in a        therapeutic effect.

This invention is also directed to a pharmaceutical combinationcomposition comprising: a therapeutically effective amount of acomposition comprising

-   -   a first compound, said first compound being a Formula I compound        or a pharmaceutically acceptable salt of said compound;    -   a second compound, said second compound being an aldose        reductase inhibitor, a glycogen phosphorylase inhibitor, a        sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase        1B inhibitor, a dipeptidyl protease inhibitor, insulin        (including orally bioavailable insulin preparations), an insulin        mimetic, metformin, acarbose, a PPAR-gamma ligand such as        troglitazone, rosaglitazone, pioglitazone, or GW-1929, a        sulfonylurea, glipazide, glyburide, or chlorpropamide; and        optionally    -   a pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a kit comprising:

-   -   a. an amount of a Formula I compound or a pharmaceutically        acceptable salt of said compound and a pharmaceutically        acceptable carrier, vehicle or diluent in a first unit dosage        form;    -   b. an amount of an aldose reductase inhibitor, a glycogen        phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a        protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease        inhibitor, insulin (including orally bioavailable insulin        preparations), an insulin mimetic, metformin, acarbose, a        PPAR-gamma ligand such as troglitazone, rosaglitazone,        pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide,        or chlorpropamide and a pharmaceutically acceptable carrier,        vehicle or diluent in a second unit dosage form; and    -   c. means for containing said first and second dosage forms        wherein the amounts of the first and second compounds result in        a therapeutic effect.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal composition can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound of the present invention effective totreat a mammal (e.g., human) having a disease or condition mediated byMCH, and thus producing the desired therapeutic effect.

The effective amount of active compound in a unit dose of preparationmay be varied or adjusted from about 0.01 mg to about 1000 mg,preferably from about 0.01 mg to about 750 mg, more preferably fromabout 0.01 mg to about 500 mg, and most preferably from about 0.01 mg toabout 250 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total dosage may bedivided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.04mg/day to about 4000 mg/day, in two to four divided doses.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

In the preparations and examples, the following abbreviations are used:room temperature (R.T.), phenyl (Ph), -t-butyloxycarbonyl (-Boc),methylamine (MeNH₂), sodium triacetoxyborohydride (NaBH(OAc)₃), ethylacetate (EtOAc), methanol (MeOH), triethylamine (Et₃N), ether (Et₂O),tetrahydrofuran (THF), diisopropylethylamine (iPr₂NEt), 1,2dimethoxyethane (DME), ethanol (EtOH),1,1′-bis(diphenylphosphino)ferrocene (dppf) and preparative thin layerchromatography (PTLC), b (broad), bs (broad singlet).

To a mixture of N-t-butoxycarbonyl-4-piperidone (10 g, 50 mmol) andaqueous methylamine (40% w/w, 10 ml) in 1,2-dichloroethane (125 ml) wasadded NaBH(OAc)₃ (16.0 g, 75 mmol). The reaction mixture was stirredovernight, then 1M NaOH (250 ml) was added and the whole was extractedwith ether (700 ml). The organic layer was washed with sat'd NaCl, dried(MgSO₄), filtered, and concentrated to give the product (10.5 g, 97%) asan oil. ¹H NMR (CDCl₃, 400 MHz) δ 4.09 (2H, m), 2.86 (2H, m), 2.55 (1H,m), 2.50 (3H, s), 1.90 (2H, m), 1.51 (9H, s), 1.30 (2H, m).

To a stirred solution of Preparation 1 (21.0 g, 83.7 mmol) and Et₃N (35ml, 252 mmol) in CH₂Cl₂ (300 ml) was added benzyl chloroformate (18 ml,126 mmol) dropwise. After 5 hr, sat'd NH₄Cl (200 ml) was added, and theorganic layer was washed with H₂O (150 ml) and sat'd NaCl (150 ml),dried (MgSO₄), filtered and concentrated. To the residue (32 g) wasadded 4N HCl in 1,4-dioxane (300 ml), and the mixture was stirred for 4hr. The reaction mixture was concentrated, acetone was added, and thereaction mixture was again concentrated. The solid residue was dissolvedin MeOH (40 ml) and Et₂O was added. The resultant precipitate wascollected, washed with Et₂O, and dried to give the product as a solid(20.2 g, 85%). MS m/e 249 (M+H⁺, free base).

Step 1

An N₂-purged mixture of Preparation 2 (1.03 g, 3.68 mmol),2-bromo-3-trifluoromethylpyridine (1.60 g, 7.08 mmol), Pd(OAc)₂ (48 mg,0.21 mmol), 1,3-bis-(diphenylphosphino)propane (0.82 g, 0.20 mmol), andsodium-t-butoxide (1.42 g, 14.8 mmol,) in toluene (10 ml) was heated at100° C. for 3 hr. The reaction mixture was allowed to cool and filteredthrough celite. The filter pad was washed with CH₂Cl₂/water, and theorganic layer was washed with sat'd NaCl, dried (MgSO₄), filtered andconcentrated. The residue was subjected to flash chromatography(gradient; CH₂Cl₂ to 1:99 MeOH/CH₂Cl₂) to give the product (1.15 g,80%). MS m/e 394 (M+H)⁺.

Step 2

A mixture of the product of Step 1 (1.08 g, 2.75 mmol) in EtOH wasstirred with 10% Pd/C (0.13 g) under an H₂ atmosphere. After one day,the catalyst was removed by filtration through Celite and the volatileswere evaporated to give the product (0.67 g, 94%). MS m/e 260 (M+H)⁺.

The following compounds were made using essentially the same procedureand the appropriate starting materials:

¹H NMR (CDCl₃, 400 MHz) δ 8.24 (1H, m), 6.8 (1H, s), 6.7 (1H, d), 4.3(2H, m), 3.0 (2H, m), 2.7 (1H, m), 2.5 (3H, s), 2.0 (2H, m), 1.6 (1H,b), 1.4 (2H, m).

¹H NMR (CDCl₃, 400 MHz) δ 8.16 (1H, m), 7.43 (1H, m), 6.64 (1H, d, J=8.6Hz), 6.56 (1H, m), 4.24 (2H, m), 2.90 (2H, m), 2.63 (1H, m), 2.47 (3H,s), 2.39 (1H, b), 2.00 (2H, m), 1.41 (1H, m). MS m/e 192 (M+H)⁺.

Step 1

An N₂-purged mixture of Preparation 2 (0.94 g, 11 mmol),2-chloro-5-fluoropyridine (0.94 g, 7.2 mmol; Synthesis, 1989, 905-908),Pd(OAc)₂ (64 mg, 0.29 mmol), (di-t-butylphosphino)biphenyl (0.16 mmol 49mg), sodium-t-butoxide (22.2 mmol, 2.13 g) and toluene (40 ml) washeated at 100° C. for 3 hr. The reaction mixture was allowed to coolthen filtered through celite, and the filter pad was washed with EtOAc.The combined filtrate and washings were washed with sat'd NaHCO₃, waterand sat'd NaCl, then dried (MgSO₄), filtered and concentrated. Theresidue was subjected to flash chromatography (gradient; CH₂Cl₂ to0.5:99.5 MeOH/CH₂Cl₂) to give the product (0.69 g, 28%). MS m/e 344(M+H)⁺.

Step 2

A mixture of the product of Step 1 (0.69 g, 2.0 mmol) and 10% Pd/C (80mg) in EtOH (20 ml) was stirred under H₂ for 3 days. The reactionmixture was filtered through celite and the volatiles evaporated toyield the product (0.49 g, 100%) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ8.0 (1H, m), 7.2 (1H, m), 6.6 (1H, m), 4.2 (2H, m), 2.9 (2H, m), 2.6(1H, m), 2.5 (3H, s), 2.0 (2H, m), 1.4 (2H, m).

The following compounds were prepared using the appropriate startingmaterials and essentially the same procedure.

¹H NMR (CDCl₃, 400 MHz) δ 8.2 (1H, m), 7.35 (1H, m), 7.15 (1H, m), 4.25(2H, m), 2.85 (2H, m), 2.65 (3H, s), 2.6 (1H, m), 2.5 (3H, s), 2.0 (2H,m), 1.9 (1H, b), 1.4 (2H, m).

¹H NMR (CDCl₃, 400 MHz) 68.29 (1H, s), 8.07 (1H, b), 7.17 (2H, m), 4.2(1H, b), 3.74 (2H, m), 2.82 (2H, m), 2.74 (3H, s), 1.70 (4H, m). MS m/e192 (M+H)⁺.

Step 1

A mixture of (3S)-(−)-3-acetamidopyrrolidine (3.04 g, 23.7 mmol),anhydrous CH₂Cl₂ (50 ml), di-tert-butyl dicarbonate (5.17 g, 23.7 mmol)and Et₃N (0.66 ml, 4.74 mmol) was stirred for 40 min., then partitionedbetween CH₂Cl₂ (200 ml) and H₂O. The organic layer was dried (Na₂SO₄),filtered and concentrated to give the product (5.17 g, 96%). ¹HNMR(CDCl₃) δ 6.10-5.90 (d, b, 1H), 4.41 (m, 1H), 3.57 (s, b, 1H), 3.38 (m,b., 2H), 3.18 (m, b., 1H), 2.10 (m, 1H), 1.96 (s, 3H), 1.92 (s, b., 1H),1.44 (s, 9H).Step 2

To a solution of the product of Step 1 (5.01 g, 21.9 mmol) in anhydrousTHF (100 ml) was added NaH (95%, 0.665 g, 26.3 mmol) and CH₃I (4.1 ml,66 mmol). The reaction mixture was stirred at R.T. for 16 hr. AdditionalNaH (60% in mineral oil, 0.263 g, 6.58 mmol) and CH₃I (4.1 ml, 65.8mmol) were added. The reaction mixture was stirred for an additional 8hr, quenched with CH₃OH (˜5 ml) and poured into H₂O (100 ml). The wholewas extracted with CH₂Cl₂ (3×200 ml) and the combined organic layerswere dried (Na₂SO₄), filtered and evaporated. Subjection of the residueto flash chromatography (1:1 then 2:1 EtOAc/hexane, then 2:98CH₃OH/CH₂Cl₂) gave the product (5.15 g, 97%). ¹HNMR (CDCl₃) (mixture ofrotamers) δ 5.10 (s, b., C-3H), 4.40 (s, b., C-3H), 3.60-3.00 (m, b.,4H), 2.89 (s) & 2.83 (s) (CH₃CO, 3H), 2.14 (s) & 2.09 (s) (CH₃N, 3H),2.10-2.80 (m, b., 2H), 1.42 (d, 9H). MS m/e 243 (M+H)⁺.

Step 3.

A mixture of the product of Step 2 (2.00 g, 8.26 mmol), CH₃OH (50 ml)and aq. 5N NaOH (6.7 ml) was refluxed for 2.5 days. The reaction mixturewas allowed to cool then poured into H₂O (50 ml). The whole wasextracted with CH₂Cl₂ (5×50 ml), and the combined organic layers weredried (Na₂SO₄), filtered and evaporated to give the product (1.40 g,85%). ¹HNMR (CDCl₃) δ 3.60-3.00 (m, 6H), 2.43 (s, 3H), 2.04 (m, 1H),1.71 (m, 1H), 1.45 (d, 9H). MS m/e 201 (M+H)⁺.

Step 1

To a stirred solution of 4-piperidone hydrate hydrochloride (40.00 g,0.260 mol) in THF (320 ml) was added CH₃SO₂Cl (31.0 ml, 0.402 mol) and15% aq. NaOH (156 ml) such that the reaction temperature was maintainedbetween 26-32° C. After the addition was complete, the reaction wasstirred at R.T. for 2 hr and transferred to a separatory funnel. Theorganic layer was collected and the aqueous layer was extracted with THF(2×250 ml). The combined organic layers were dried (Na₂SO₄). Afterfiltration, the concentrated residue was washed with hexane to give theproduct (46.00 g, 100%) as a solid. ¹H NMR (CDCl₃) δ 3.59 (t, J=6.00 Hz,4H), 2.89 (s, 3H), 2.59 (t, J=5.6 Hz, 4H).

Step 2

A mixture of the product of Step 1 (40.00 g, 0.226 mol), CH₃CN (240 ml),and 40% CH₃NH₂ (20.4 ml, 0.263 mol) was stirred at R.T. for 1 hr. Themixture was slowly added to a −10° C. solution of NaBH(OAC)₃ (60.00 g,0.283 mol) in CH₃CN (120 ml). After the addition was complete, thereaction was allowed to attain R.T. After 16 hr the reaction mixture wasevaporated to a small volume, and 1N aq. NaOH (282 ml) was added. Theresulting solution was extracted with CH₂Cl₂ (3×500 ml), then withtoluene. The combined organic layers were dried (Na₂SO₄), filtered andevaporated to give the product (29.00 g, 63%) as a solid. ¹H NMR (CDCl₃)δ 3.66 (m, 2H), 2.84 (m, 2H), 2.76 (s, 3H), 2.52 (m, 1H), 2.42 (s, 3H),1.96 (m, 2H), 1.45 (m, 2H). MS m/e 193 (M+H)⁺

Step 1

A mixture of 4-piperidone ethylene ketal (0.64 ml, 5.0 mmol) andsulfamide (0.53 g, 5.5 mmol) in DME (20 ml) was refluxed for 16 hr. Themixture was concentrated to ca. 3 ml, dissolved in EtOAc (175 ml),washed with sat'd NH₄Cl (2×25 ml), water (2×25 ml), and brine (25 ml).The organic portion was dried, filtered, and evaporated to give theproduct (0.58 g, 52%). MS (ES) m/e 223 (M+H)⁺.Step 2

A mixture of the product of Step 1 (560 mg, 2.52 mmol) and pyridinium4-toluenesulfonate (190 mg, 0.756 mmol) in acetone (25 ml) and water(0.5 ml) was refluxed for 64 hr. The mixture was evaporated to drynessand the residue was partitioned between CH₂Cl₂ (75 ml) and aq. NaHCO₃(2×20 ml). The aqueous layer was extracted with CH₂Cl₂ and EtOAcsequentially. The EtOAc layer was evaporated to give the product (140mg). ¹H NMR (CD₃OD, 400 MHz) δ 3.47 (1H, t, J=6.4 Hz), 3.15 (3H, m),2.54 (1H, t, J=6.4 Hz), 1.81 (3H, m).

Step 3

A mixture of the product of Step 2 (135 mg, 0.757 mmol), 40% aqueousmethylamine (0.3 ml, 2.4 mmol), and NaBH(OAc)₃ (375 mg, 1.77 mmol) in1,2-dichloroethane (5 ml) was stirred at R.T. for 19 hr. The mixture waspartitioned between 3N NaOH (5 ml) and EtOAc (3×50 ml). The organiclayer was concentrated to give the crude product (40 mg). The aqueouslayer was evaporated to dryness and the residue was suspended in EtOAc.The suspension was filtered and the filtrate concentrated to giveanother batch of the product (70 mg). MS (FAB) m/e 194 (M+H)⁺.

To a stirred mixture of 1,4-cyclohexanedione monoethylene ketal (4.68 g,30 mmol) and 40% aq. methylamine (6.0 ml) in 1,2-dichloroethane (75 ml),was added NaBH(OAc)₃ (9.6 g, 45 mmol) in portions. The reaction mixturewas vigorously stirred for 16 hr, then 1N NaOH (75 ml) was added. Theorganic layer was washed with sat'd NaCl, dried (MgSO₄), filtered, andevaporated to give an oil (4.60 g, 90%) that was used without furtherpurification. ¹H NMR (CDCl₃, 400 MHz) δ 3.97 (4H, s), 2.47 (1H, m), 2.46(3H, s), 1.91 (2H, m), 1.80 (2H, m), 1.59 (2H, m), 1.45 (2H, m).

EXAMPLE 1

Step 1

An N₂-purged mixture of 3,5-difluorophenylboronic acid (7.76 g, 24mmol), 2-bromo-5-nitropyridine (2.46 g, 12 mmol), Pd(dppf)Cl₂.CH₂Cl₂(0.40 g, 0.48 mmol), potassium phosphate (5.06 g, 23.9 mmol) and1,2-dimethoxyethane (40 ml) was heated in a sealed tube at 80° C. for 5hr. The reaction mixture was allowed to cool, filtered through celite,and the filtrate was concentrated. The residue was partitioned betweensat'd Na₂CO₃ and EtOAc, and the organic layer was washed with water andsat'd NaCl, dried (MgSO₄), filtered and concentrated. Flashchromatography of the residue (1:99 EtOAc/hexane) to gave the product(2.16 g, 76%). MS m/e 237 (M+H)⁺.Step 2

The product of Step 1 (240 mg, 1.0 mmol), 10% Pd/C (38 mg), and EtOH (25ml) were stirred under an H₂ atmosphere for 3 days. The reaction mixturewas filtered through celite and the volatiles were evaporated to givethe product (171 mg, 83%). MS m/e 207 (M+H)⁺.

Step 3

A mixture of the product of Step 2 (145 mg, 0.70 mmol), triphosgene (70mg, 0.24 mmol), and iPr₂NEt (0.61 ml, 3.5 mmol) in toluene (5 ml) washeated at 110° C. for 2 hr. The reaction mixture was allowed to cool andPreparation 5 (140 mg, 0.73 mmol) was added. After 16 hr, the reactionmixture was concentrated, and partitioned between CH₂Cl₂ (40 ml) and H₂O(20 ml). The organic layer was dried (MgSO₄), filtered and evaporated.The residue was subjected to PTLC (5:95 MeOH/CH₂Cl₂) to give the product(148 mg, 50%). ¹H NMR (CDCl₃, 400 MHz) δ 8.51 (1H, d, J=2.8 Hz), 8.18(2H, m), 7.64 (1H, d, J=8.8 Hz), 7.50 (3H, m), 6.80 (1H, m), 6.70 (1H,d, J=8.8 Hz), 6.63 (1H, dd, J=7.1, 4.9 Hz), 6.54 (1H, s), 4.54 (1H, m),4.45 (2H, m), 2.94 (2H, m), 2.93 (3H, s), 1.80-1.73 (4H, m). MS (m/e)424 (M+H)⁺.

EXAMPLE 2

Step 1

Reaction of 5-chlorothiophene-2-boronic acid with2-chloro-5-nitropyridine by essentially the procedure of Example 1, Step1 gave the product. MS m/e 241 (M+H)⁺.Step 2

To an ice-cold suspension of the product of Step 1 (400 mg, 1.66 mmol)and NiCl₂.6H₂O (790 mg, 3.3 mmol) in MeOH (20 ml) was added NaBH₄ (252mg, 6.67 mmol) in portions. After 20 min., H₂O (10 ml) and CH₂Cl₂ (20ml) were added, and the whole was filtered through celite. The organiclayer was dried (Na₂SO₄), filtered and concentrated to give a solid (286mg, 82%). ¹H NMR (CDCl₃, 400 MHz) δ 8.02 (1H, d, J=2.9 Hz), 7.38 (1H, d,J=8.4 Hz), 7.12 (1H, dd, J=3.8, 0.4 Hz), 6.98 (1H, dd, J=8.7, 2.7 Hz),6.85 (1H, dd, J=3.8, 0.4 Hz), 3.76 (2H, b).

Step 3

To an ice-cold solution of the product of Step 2 (50 mg, 0.24 mmol) andpyridine (0.06 ml, 0.7 mmol) in THF (5 ml) was added N,N′-disuccinimidylcarbonate (60 mg, 0.24 mmol) and the reaction mixture was allowed towarm to R.T. After 1 hr, Preparation 5 (52 mg, 0.26 mmol) was added andthe reaction mixture was stirred for 2 hr. The reaction mixture waspoured into H₂O (20 ml) and extracted with CH₂Cl₂. The organic layer wasdried (MgSO₄), filtered and evaporated. The residue was subjected toPTLC (5:95 MeOH/CH₂Cl₂) to give the product (84 mg, 82%). ¹H NMR (CDCl₃,400 MHz) δ 8.32 (1H, d, J=2.6 Hz), 8.16 (1H, m), 8.03 (1H, dd, J=8.6,2.1 Hz), 7.46 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=4.0, 0.6 Hz), 6.91 (1H,s), 6.86 (1H, dd, J=8.7, 2.7 Hz), 6.85 (1H, dd, J=4.0, 0.6 Hz), 6.65(1H, d, J=8.1 Hz), 6.60 (1H, m), 4.45 (1H, m), 4.38 (2H, m), 2.87 (2H,m), 2.84 (3H, s), 1.74-1.66 (4H, m).

EXAMPLE 3

Step 1

A mixture of the product from Example 1, Step 2 (1-2) (500 mg, 2.43mmol), triphosgene (240 mg, 0.81 mmol) and iPr₂NEt (2.1 ml, 12 mmol) intoluene (15 ml) was heated at reflux for 2 hr. The reaction mixture wasallowed to cool to R.T. and Preparation 1 (880 mg, 4.1 mmol) was added.The reaction mixture was stirred for 24 hr, diluted with CH₂Cl₂, andwashed with sat'd NaHCO₃, H₂O, and sat'd NaCl. The organic layer wasdried (Na₂SO₄), filtered and concentrated. Flash chromatography of theresidue (gradient; CH₂Cl₂ to 1.5:98.5 MeOH/CH₂Cl₂) gave the product (650mg, 60%). ¹H NMR (CDCl₃) δ 8.49 (d, J=2.5 Hz, 1H), 8.12 (m, 1H), 7.60(d, J=8.8 Hz, 1H), 7.46 (m, 2H), 6.78 (m, 1H), 6.74 (s, 1H), 4.40 (m,1H), 4.20 (m, 2H), 2.90 (s, 3H), 2.78 (m, 2H), 1.67-1.55 (m, 4H), 1.45(s, 9H). MS m/e 447 (M+H)⁺.Step 2

To a solution of the product of Step 1, 3-1, (510 mg, 1.14 mmol) in THF(15 ml) was added 2N HCl (10 ml). After 6 hr, the volatiles wereevaporated and the residue was washed with ether (3×10 ml) to give theproduct (480 mg, 100%). ¹H NMR (CD₃OD) δ 9.28 (s, 1H), 8.69 (d, J=8.8Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 7.60 (d, J=5.8 Hz, 2H), 7.30 (t, 1H),4.49 (m, 1H), 3.52 (d, 2H), 3.18 (t, 2H), 3.04 (s, 3H), 2.12 (m, 2H),1.97 (m, 2H). MS m/e 347 (M+H)⁺.

Step 3

To the product from Step 2 (0.19 mmol, 80 mg) in CH₂Cl₂ (2 ml) was addedEt₃N (0.7 mmol, 0.1 ml) and methanesulfonyl chloride (0.44 mmol, 50 mg).The reaction was stirred at R.T. for 1 hr, concentrated, and the residuewas subjected to PTLC (5:95 MeOH/CH₂Cl₂) to give the product (70 mg,87%). ¹H NMR (CDCl₃, 400 MHz) δ 8.50 (1H, d), 8.15 (1H, m), 7.7 (1H, d),7.5 (2H, m), 6.8 (1H, m), 6.65 (1H, b), 4.5 (1H, m), 3.95 (2H, m), 3.0(3H, s), 2.8 (5H, m), 1.8 (4H, m). MS m/e 425 (M+H)⁺.

EXAMPLE 4

To a solution of the amine 3-2 (51 mg, 0.12 mmol) in CH₂Cl₂ (2 ml) wasadded Et₃N (0.1 ml, 0.7 mmol) and cyclopropylcarbonyl chloride (0.02 ml,0.2 mmol). The reaction mixture was stirred at R.T. for 40 min. thensubjected directly to PTLC (5:95 MeOH/CH₂Cl₂) to give the product (49mg, 99%). ¹H NMR (CDCl₃, 400 MHz) δ 8.50 (1H, m), 8.16 (1H, m), 7.65(1H, m), 7.49 (2H, m), 6.82 (1H, m), 6.57 (1H, b), 4.75 (1H, m), 4.56(1H, m), 4.32 (1H, b), 3.21 (1H, m), 2.93 (3H, s), 2.66 (1H, m), 1.80(5H, m), 0.99 (2H, m), 0.77 (2H, m). MS m/e 415 (M+H)⁺.

Using the appropriate reagents and Preparations the following Exampleswere prepared by essentially the same procedures: STRUCTURE ¹H NMR MS(M + H)⁺

(CDCl₃) δ 8.52 (d, J = 2.5 Hz, 1H), 8.43 (m, 1H), 8.17 (m, 1H), 7.94 (m,2H), 7.86 (m, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.45 (1, 2H), 7.39 (t, 1H),7.01 (m, 1H), 6.60 (s, 1H), 4.47 (m, 1H), 3.68 (d, b, 2H), 3.04 (t, 2H),2.98 (s, 3H), 1.87 (m, 2H), 1.78 (m, 2H). 456 1A

(CDCl₃) δ 8.57 (d, J = 2.5 Hz, 1H), 8.30 (m, 1H), 8.18 (m, 1H), 7.93 (d,2H), 7.70 (d, 1H), 7.43 (t, 2H), 7.39 (m, 1H), 6.82 (s, 1H), 6.77 (m,1H), 6.58 (s, 1H), 4.59 (m, 1H), 4.48 (m, 2H), 3.01 (m, 2H), 2.96 (s,3H), 1.83 (m, 2H), 1.70 (m, 2H). 456 1B

(CDCl₃) δ 8.50 (d, J = 2.6 Hz, 1H), 8.17 (s, 2H), 8.14 (m, 1H), 7.94 (m,2H), 7.68 (d, J = 8.8 Hz, 1H), 7.44 (t, 2H), 7.38 (m, 1H), 6.59 (s, 1H),4.86 (m, 2H), 4.54 (m, 1H), 2.93 (m, 2H), 2.89 (s, 3H), 2.45 (q, 2H),1.76 (m, 2H), 1.64 (m, 2H), 1.19 (t, 3H). 417 1C

(CDCl₃) δ 8.50 (d, J = 2.7 Hz, 1H), 8.10 (m, 1H), 7.91 (d, J = 7.3Hz,2H), 7.65 (d, J = 8.6 Hz, 1H), 7.43 (t, 2H), 7.37 (m, 1H), 6.63 (s, 1H),4.24 (m, 1H), 2.94-2.90 (m, 5H), 2.28 (s, 3H), 2.05 (m, 2H), 1.82-1.64(m, 4H). 325 1D

(CDCl₃) δ 8.51 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.11 (m,2H), 7.93 (d, J =8.4 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.45 (t, 2H),7.38 (m, 1H), 7.18 (m, 2H), 6.72 (s, 1H), 4.46 (m, 1H), 3.77 (m, 2H),2.94 (s, 3H), 2.89 (m, 2H), 1.81 (m, 4H). 388 1E

(CDCl₃) δ 8.51 (d, J = 2.2 Hz, 1H), 8.19 (m, 1H), 8.15 (m, 1H), 7.95 (d,J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.50-7.37 (m, 4H), 6.70-6.56(m, 3H), 4.53 (m, 1H), 4.43 (m, 2H), 2.98-2.90 (m, 5H), 1.78-1.71 (m,4H). 388 1F

(CDCl₃) δ 8.51 (m, 1H), 8.17 (m, 1H), 7.66 (d, 1H), 7.50 (m, 2H), 7.38(t, 1H), 6.80 (m, 1H), 6.49 (m, 3H), 4.45 (m, 3H), 2.91 (m, 5H), 2.40(s, 3H), 1.83-1.70 (m, 4H). 438 1G

(CDCl₃) δ 8.53 (m, 1H), 8.18 (m, 1H), 8.04 (d, 1H), 7.66 (d, 1H), 7.50(m, 2H), 7.26 (m, 1H), 6.80 (m, 1H), 6.65 (m, 1H), 6.53 (s, 1H), 4.50(m, 1H), 4.29 (m, 2H), 2.91 (m, 5H), 1.83-1.67 (m, 4H). 442 1H

(CDCl₃) δ 8.51 (m, 1H), 8.14 (m, 1H), 7.64 (m, 1H), 7.48 (m, 2H), 7.19(m, 1H), 6.80 (m, 1H), 6.58 (m, 1H), 6.53 (s, 1H), 4.54 (m, 1H), 4.13(m, 2H), 3.13 (m, 2H), 2.94 (s, 3H), 1.82 (m, 4H). 430 1I

(CDCl₃) δ 8.32 (d, J = 2.2 Hz, 1H), 8.08 (m, 1H), 7.50 (d, J = 8.7 Hz,1H), 7.23 (d, J = 4.1 Hz, 1H), 6.88 (d, J = 4.0 Hz, 1H), 6.58 (s, 1H),4.40 (m, 1H), 4.32 (m, 2H), 2.90 (s, 3H), 2.78 (m, 2H), 1.68-1.50 (m,4H), 1.46 (s, 9H). 451 2A

(CDCl₃) δ 8.39 (d, J = 2.4 Hz, 1H), 8.07 (m, 1H), 7.52 (d, J = 8.8 Hz,1H), 7.26 (m, 1H), 6.90 (d, J = 4.0 Hz 1H), 6.60 (s, 1H), 4.42 (m, 1H),3.92 (m, 2H), 2.94 (s, 3H), 2.80 (m, 5H), 1.84-1.79 (m, 4H). 429 2B

(CDCl₃) δ 8.38 (s, 1H), 8.08 (m, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.27 (m,1H), 6.90 (d, J = 3.8 Hz, 1H), 6.55 (bs, 1H), 4.45 (m, 1H), 3.92 (m,2H), 2.94 (m, 7H), 1.84-1.76 (m, 4H), 1.37 (t, 3H). 443 2C

(CDCl₃) δ 8.58 (s, b, 1H), 8.10 (m, 1H), 7.95 (m, 2H), 7.70 (m, 1H),7.43 (t, 2H), 7.39 (m, 1H), 6.57 (s, b, 1H), 4.42 (m, 1H), 3.83 (m, 2H),2.94 (s, 3H), 2.82 (m, 5H), 1.82 (m, 4H). 389 3A

(CDCl₃) δ 8.60 (s, 1H), 8.15 (m, 1H), 7.93 (m, 2H), 7.70 (d, J = 8.8 Hz,1H), 7.46 (t, 2H), 7.39 (m, 1H), 6.64 (s, b, 1H), 4.47 (m, 1H), 3.93 (m,2H), 2.96 (m, 7H), 1.80 (m, 4H), 1.37 (t, 3H). 403 3B

(CDCl₃) δ 8.52 (d, J = 2.6 Hz, 1H), 8.10 (m, 1H), 7.93 (m, 2H), 7.68 (d,J = 8.8 Hz, 1H), 7.49-7.35 (m, 3H), 6.58 (s, 1H), 4.46 (m, 1H), 3.95 (m,2H), 3.18 (m, 1H), 3.03-2.85 (m, 5H), 1.76 (m, 4H), 1.33 (d, 6H). 417 3C

(CDCl₃) δ 8.55 (d, J = 2.4 Hz, 1H), 8.10 (m, 1H), 7.93 (m, 2H), 7.68 (d,J = 8.8 Hz, 1H), 7.46-7.36 (m, 3H), 6.64 (s, 1H), 4.44 (m, 1H), 3.91 (m,2H), 2.93-2.82 (m, 7H), 1.86-1.76 (m, 6H), 1.06 (t, 3H). 417 3D

(CD₃OD) δ 9.20 (d, J = 2.4 Hz, 1H), 8.53 (m, 1H), 8.25 (d, J = 9.2 Hz,1H), 7.58 (m, 2H), 7.29 (m, 1H), 4.30 (m, 1H), 3.86 (m, 2H), 3.00 (m,5H), 2.50 (m, 1H), 1.95-1.78 (m, 4H), 1.05 (m, 4H). 451 3E

(CDCl₃) δ 8.52 (d, J = 2.4 Hz, 1H), 8.12 (m, 1H), 7.63 (d, J = 8.8 Hz,1H), 7.49 (m, 2H), 6.80 (m, 1H), 6.59 (s, 1H), 4.45 (m, 1H), 3.93 (m,2H), 2.93 (m, 7H), 1.79 (m, 4H), 1.36 (t, 3H). 439 3F

(CD₃OD) δ 9.21 (d, J = 2.4 Hz, 1H), 8.55 (m, 1H), 8.25 (d, J = 9.2 Hz,1H), 7.59 (m, 2H), 7.28 (m, 1H), 4.30 (m, 1H), 3.85 (m, 2H), 2.95 (m,7H), 1.81 (m, 6H), 1.07 (t, 3H). 453 3G

(CDCl₃) δ 8.52 (d, J = 2.4 Hz, 1H), 8.13 (m, 1H), 7.63 (d, J = 8.8 Hz,1H), 7.49 (m, 2H), 6.81 (m, 1H), 6.57 (s, 1H), 4.47 (m, 1H), 3.93 (m,2H), 3.18 (m, 1H), 2.99 (m, 2H), 2.95 (s, 3H), 1.78 (m, 4H), 1.33 (d,6H). 453 3H

(CDCl₃) δ 8.59 (d, J = 2.4 Hz, 1H), 8.07 (m, 1H), 7.78 (m, 1H), 7.71 (m,1H), 7.28 (m, 2H), 6.53 (s, 1H), 4.44 (m, 1H), 3.91 (m, 2H), 2.96 (s,3H), 2.79 (m, 5H), 1.82 (m, 4H). 425 3I

(CDCl₃) δ 8.59 (d, J = 2.4 Hz, 1H), 8.06 (m, 1H), 7.78 (m, 1H), 7.71 (m,1H), 7.07 (m, 1H), 7.02 (m, 1H), 6.54 (s, 1H), 4.46 (m, 1H), 3.93 (d, J= 11.2 Hz, 2H), 2.94 (m, 7H), 1.80 (m, 4H), 1.37 (t, 3H). 439 3J

(CDCl₃) δ 8.60 (s, 1H), 8.06 (m, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.68 (m,1H), 7.07 (m, 1H), 7.01 (m, 1H), 6.66 (s, 1H), 4.43 (s, 1H), 3.90 (d,2H), 2.91 (m, 5H), 2.60 (m, 1H), 1.78 (m, 4H), 1.15 (m, 2H), 1.00 (m,2H). 451 3K

(CDCl₃) δ 8.61 (s, 1H), 8.06 (m, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.71 (m,1H), 7.07 (m, 1H), 7.01 (m, 1H), 6.64 (s, 1H), 4.44 (m, 1H), 3.91 (d, J= 12.4 Hz, 2H), 2.93 (s, 3H), 2.86 (m, 4H), 1.82 (m, 6H), 1.06 (t, 3H).453 3L

(CD₃OD) δ 9.20 (m, 1H), 8.55 (m, 1H), 8.25 (m, 1H), 7.71 (m, 3H), 7.41(m, 1H), 4.29 (m, 1H), 3.85 (m, 2H), 3.01 (s, 3H), 2.87 (m, 5H),1.94-1.76 (m, 4H). 407 3N

(CDCl₃) δ 8.52 (d, J = 2.5 Hz, 1H), 8.12 (m, 1H), 7.71 (m, 3H), 7.38 (m,1H), 7.07 (m, 1H), 6.47 (m, 1H), 4.43 (s, 1H), 3.92 (d, 2H), 2.96 (m,5H), 2.28 (m, 1H), 1.81 (m, 4H), 1.17 (m, 2H), 1.00 (m, 2H). 433 3O

(CDCl₃) δ 8.51 (d, J = 2.6 Hz, 1H), 8.13 (m, 1H), 7.93 (d, J = 7.3 Hz,2H), 7.68 (d, J = 8.6 Hz, 1H), 7.45 (1, 2H), 7.38 (m, 1H), 6.61 (s, 1H),4.42 (m, 1H), 4.20 (m, 2H), 2.91 (s, 3H), 2.79 (m, 2H), 1.76-1.55 (m,4H), 1.45 (s, 9H). 411 4A

(CDCl₃) δ 8.69 (d, J = 5.3 Hz, 2H), 8.55 (d, J = 2.7 Hz, 1H), 8.14 (m,1H), 7.62 (m, J =8.6 Hz, 1H), 7.47 (m, 2H), 7.28 (m, 2H), 6.95 (s, 1H),6.79 (m, 1H), 4.82 (m, 1H), 4.56 (m, 1H), 3.68 (m, 1H), 3.17 (m, 1H),2.94 (s, 3H), 2.85 (m, 1H), 1.90-1.45 (m, 4H). 452 4B

(CDCl₃) δ 8.68 (m, 2H), 8.55 (m, 1H), 8.12 (m, 1H), 7.78 (m, 1H), 7.64(d, J = 8.6 Hz, 1H), 7.47 (m, 2H), 7.37 (m, 1H), 6.82 (m, 1H), 6.65 (s,1H), 4.86 (m, 1H), 4.59 (m, 1H), 3.82 (m, 1H), 3.22 (m, 1H), 2.96 (s,3H), 2.85 (m, 1H), 1.90-1.45 (m, 4H). 452 4C

(CDCl₃) δ 8.50 (d, J = 2.8 Hz, 1H), 8.12 (m, 1H), 7.62 (d, J = 8.8 Hz,1H), 7.45 (m, 2H), 6.80 (m, 2H), 4.75 (m, 1H), 4.50 (m, 1H), 3.90 (m,1H), 3.18 (m, 1H), 2.90 (s, 3H), 2.59 (m, 1H), 2.11 (s, 3H), 1.80-1.56(m, 4H). 389 4D

(CDCl₃) δ 8.50 (d, J = 2.0 Hz, 1H), 8.13 (m, 1H), 7.62 (d, J = 8.8 Hz,1H), 7.46 (m, 2H), 6.78 (m, 2H), 4.76 (m, 1H), 4.51 (m, 1H), 3.92 (m,1H), 3.11 (m, 1H), 2.90 (s, 3H), 2.59 (m, 1H), 2.35 (q, 2H), 1.76-1.54(m, 4H), 1.15 (m, 3H). 403 4E

(CD₃OD) δ 9.26 (d, J = 2.4 Hz, 1H), 8.59 (m, 1H), 8.29 (d, J = 8.8 Hz,1H), 7.60 (m, 2H), 7.32 (m, 1H), 4.70 (m, 1H), 4.39 (m, 1H), 4.10 (m,1H), 3.21 (m, 1H), 2.98 (s, 3H), 2.71 (m, 1H), 2.42 (m, 2H), 1.79-1.62(m, 6H), 0.99 (m, 3H). 417 4F

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.15 (m, 1H), 7.61 (d, J = 8.4 Hz,1H), 7.47 (m, 2H), 6.87 (s, 1H), 6.78 (m, 1H), 4.76 (m, 1H), 4.50 (m,1H), 4.05 (m, 1H), 3.11 (m, 1H), 2.90 (s, 3H), 2.80 (m, 1H), 2.59 (m,1H), 1.82-1.54 (m, 4H), 1.13 (m, 6H). 417 4G

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.14 (m, 1H), 7.66 (d, J = 6.4 Hz,1H), 7.49 (m, 2H), 6.81 (m, 1H), 6.49 (s, 1H), 4.76 (m, 2H), 4.12 (m,1H), 3.25 (m, 1H), 2.95 (s, 3H), 2.86 (m, 1H), 1.89-1.60 (m, 4H). 443 4H

(CDCl₃) δ 8.50 (d, J = 2.0 Hz, 1H), 8.13 (m, 1H), 7.62 (d, J = 8.4 Hz,1H), 7.46 (m, 2H), 6.80 (m, 2H), 4.70 (m, 1H), 4.52 (m, 1H), 4.10 (q,2H), 3.94 (m, 1H), 3.42 (s, 3H), 3.10 (m, 1H), 2.90 (s, 3H), 2.64 (m,1H), 1.79-1.57 (m, 4H). 419 4I

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.12 (m, 1H), 7.64 (d, J = 8.8 Hz,1H), 7.47 (m, 2H), 6.80 (m, 1H), 6.67 (s, 1H), 4.79 (m, 1H), 4.56 (m,1H), 3.86 (m, 1H), 3.24 (m, 3H), 2.96 (s, 3H), 2.67 (m, 1H), 1.85-1.59(m, 4H). 457 4J

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.15 (m, 1H), 7.63 (d, J = 8.8 Hz,1H), 7.46 (m, 3H), 7.30 (d, 1H), 7.03 (m, 1H), 6.80 (m, 2H), 4.59 (m,3H), 3.06 (m, 2H), 2.93 (s, 3H), 1.81-1.64 (m, 4H). 457 4K

(CDCl₃) δ 8.49 (d, J = 2.0 Hz, 1H), 8.15 (m, 1H), 7.62 (d, J = 8.8 Hz,1H), 7.47 (m, 2H), 6.80 (m, 1H), 6.69 (s, 1H), 4.42 (m, 1H), 3.77 (m,2H), 2.92-2.83 (m, 11H), 1.68 (m, 4H). 418 4L

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.14 (m, 1H), 7.61 (d, J = 8.0 Hz,1H), 7.45 (m, 2H), 6.80 (m, 2H), 4.40 (m, 1H), 3.72 (m, 2H), 3.20 (m,4H), 2.90 (s, 3H), 2.84 (m, 2H), 1.70 (m, 4H), 1.11 (m, 6H). 446 4M

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.15 (m, 1H), 7.62 (d, J = 8.8 Hz,1H), 7.45 (m, 2H), 6.79 (m, 2H), 4.76 (m, 1H), 4.50 (m, 1H), 3.78 (m,1H), 3.26 (m, 1H), 3.04 (m, 1H), 2.90 (s, 3H), 2.60 (m, 1H), 2.35-2.13(m, 4H), 1.99-1.42 (m, 6H). 429 4N

(CDCl₃) δ 8.50 (d, J = 2.8 Hz, 1H), 8.15 (m, 1H), 7.64 (d, J = 8.8 Hz,1H), 7.49 (m, 2H), 6.80 (m, 1H), 6.54 (s, 1H), 4.80 (m, 1H), 4.54 (m,1H), 4.06 (m, 1H), 3.13 (m, 1H), 2.90 (m, 4H), 2.61 (m, 1H), 1.82-1.55(m, 12H). 443 4O

(CDCl₃) δ 8.50 (d, J = 2.8 Hz, 1H), 8.15 (m, 1H), 7.63 (d, J = 8.8 Hz,1H), 7.46 (m, 2H), 6.79 (m, 2H), 4.74 (m, 1H), 4.52 (m, 1H), 4.00 (m,1H), 3.11 (m, 1H), 2.91 (s, 3H), 2.52 (m, 2H), 1.79-1.24 (m, 14H). 4574P

(CDCl₃) δ 8.50 (m, 1H), 8.15 (m, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.49 (m,3H), 7.33-7.19 (m, 2H), 6.80 (m, 1H), 6.50 (s, 1H), 4.91 (m, 1H), 4.58(m, 1H), 3.50 (m, 1H), 3.21 (m, 1H), 2.94 (s, 3H), 2.86 (m, 1H),1.87-1.67 (m, 4H). 519 4Q

(CDCl₃) δ 8.50 (m, 1H), 8.15 (m, 1H), 7.83 (m, 1H), 7.65 (d, J = 8.8 Hz,1H), 7.50 (m, 2H), 7.41 (m, 1H), 7.24 (m, 1H), 7.10 (m, 1H), 6.80 (m,1H), 6.48 (s, 1H), 4.92 (m, 1H), 4.60 (m, 1H), 3.50 (m, 1H), 3.21 (m,1H), 2.96 (s, 3H), 2.85 (m, 1H), 1.98-1.50 (m, 4H). 577 4R

(CDCl₃) δ 8.74 (d, J = 2.4 Hz, 1H), 8.58 (m, 1H), 8.50 (d, J = 2.0 Hz,1H), 8.15 (m, 1H), 7.92 (m, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.50 (m, 2H),6.80 (m, 1H), 6.50 (s, 1H), 4.86 (m, 1H), 4.62 (m, 1H), 3.80 (m, 1H),3.21 (m, 1H), 2.97 (s, 3H), 2.88 (m, 1H), 1.94-1.70 (m, 4H). 530 532 4S

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.14 (m, 1H), 7.64 (d, J = 8.8 Hz,1H), 7.50 (m, 2H), 7.35 (d, 1H), 6.99 (d, 1H), 6.80 (m, 1H), 6.60 (s,1H), 4.80 (m, 1H), 4.60 (m, 1H), 3.80 (m, 1H), 3.21 (m, 2H), 2.94 (s,3H), 1.77 (m, 4H). 535 537 4T

(CDCl₃) δ 8.51 (m, 1H), 8.10 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.47 (m,2H), 7.33 (m, 2H), 7.25 (m, 1H), 6.84 (s, 1H), 6.77 (m, 1H), 4.92 (m,1H), 4.56 (m, 1H), 3.41 (m, 1H), 3.20 (m, 1H), 2.90 (s, 3H), 2.87 (m,1H), 1.83-1.67 (m, 4H). 519 4U

(CDCl₃) δ 8.50 (d, J = 2.4 Hz, 1H), 8.13 (m, 1H), 7.62 (d, J = 8.4 Hz,1H), 7.46 (m, 2H), 6.83 (s, 1H), 6.78 (m, 1H), 4.64 (m, 2H), 4.52 (m,1H), 2.89 (s, 3H), 2.84 (m, 2H), 2.04-1.54 (m, 19H). 509 4V

(CDCl₃) δ 8.52 (m, 1H), 8.15 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.48 (m,2H), 6.80 (m, 1H), 6.69 (s, 1H), 6.63 (m, 2H), 4.82 (m, 1H), 4.56 (m,1H), 3.86 (m, 10H), 3.15 (m, 1H), 2.94 (m, 4H), 1.76 (m, 4H). 541 4W

(CDCl₃) δ 8.51 (m, 2H), 8.15 (m, 1H), 7.92 (m, 3H), 7.65 (m, 2H), 7.50(m, 4H), 6.80 (m, H), 6.51 (s, H), 4.92 (m, 1H), 4.60 (m, 1H), 3.98 (m,1H), 3.21 (m, 1H), 2.97 (m, 4H), 1.88-1.50 (m, 4H). 501 4X

(CDCl₃) δ 8.57 (d, J = 2.8 Hz, 1H), 8.11 (m, 1H), 7.80 (m, 1H), 7.74 (m,1H), 7.08 (m, 1H), 7.01 (m, 1H), 6.50 (s, 1H), 4.44 (m, 1H), 4.22 (m,2H), 2.92 (s, 3H), 2.81 (m, 2H), 1.71-1.57 (m, 4H), 1.47 (s, 9H). 447 4Y

(CD₃OD) δ 9.30 (d, J = 2.4 Hz, 1H), 9.09 (s, 1H), 8.97 (d, J = 5.6 Hz,1H), 8.74 (d, J = 8.4 Hz, 1H), 8.65 (m, 1H), 8.19 (m, 2H), 7.62 (m, 1H),7.45 (m, 2H), 4.80 (m, 1H), 4.50 (m, 1H), 3.76 (m, 1H), 4.46 (m, 1H),3.38 (m, 1H), 3.04 (s, 4H), 2.00-1.65 (m, 4H). 452 4Z

(CDCl₃) δ 8.57 (m, 1H), 8.10 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.71 (m,1H), 7.08 (m, 1H), 7.01 (m, 1H), 6.52 (s, 1H), 4.75 (m, 1H), 4.56 (m,1H), 4.33 (m, 1H), 3.21 (m, 1H), 2.91 (s, 3H), 2.66 (m, 1H), 1.82-1.62(m, 5H), 0.99 (m, 2H), 0.78 (m, 2H). 415 4AA

(CDCl₃) δ 8.57 (d, J = 2.8 Hz, 1H), 8.09 (m, 1H), 7.78 (d, J = 8.0 Hz,1H), 7.69 (m, 1H), 7.07 (m, 1H), 7.01 (m, 1H), 6.64 (s, 1H), 4.47 (m,1H), 4.53 (m, 1H), 3.94 (m, 1H), 3.13 (t, 1H), 2.91 (s, 3H), 2.60 (t,1H), 2.33 (t, 2H), 1.78-1.54 (m, 6H), 0.96 (t, 3H). 417 4BB

(CD₃OD) δ 8.29 (d, J = 2.0 Hz, 1H), 8.60 (m, 1H), 8.19(d, J = 9.2 Hz,1H), 7.61 (m, 1H), 7.45 (m, 2H), 4.70 (m, 1H), 4.41 (m, 1H), 4.18 (m,1H), 3.21 (m, 1H), 2.93 (s, 4H), 2.69 (m, 1H), 1.77 (m, 4H), 1.14-1.09(m, 6H). 417 4CC

(CDCl₃) δ 8.57 (s, 1H), 8.08 (m, 1H), 7.76 (d, J = 6.8 Hz, 1H), 7.68 (m,1H), 7.10 (m, 1H), 7.02 (m, 1H), 6.80 (s, 1H), 4.75 (d, 1H), 4.51 (m,1H), 3.88 (d, 1H), 3.16 (t, 1H), 2.90 (s, 3H), 2.59 (1, 1H), 2.11 (s,3H), 1.80-1.56 (m, 4H). 389 4DD

(CDCl₃) δ 8.56 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 7.2 Hz,1H), 7.68 (m, 1H), 7.08 (m, 1H), 7.01 (m, 1H), 6.72 (s, 1H), 4.77 (d,1H), 4.51 (m, 1H), 3.94 (d, 1H), 3.11 (t, 1H), 2.90 (s, 3H), 2.60 (t,1H), 2.34 (q, 2H), 1.80-1.54 (m, 4H), 1.15 (t, 3H). 403 4EE

(CDCl₃) δ 8.89 (s, 1H), 8.62 (s, 1H), 8.12 (m, 1H), 8.07 (s, 1H), 7.80(d, J = 6.4 Hz, 1H), 7.70 (m, 1H), 7.11 (m, 1H), 7.01 (m, 1H), 6.64 (bs,1H), 4.80-4.20 (m, 3H), 3.35-2.80 (m, 5H), 1.86-1.69 (m, 4H). 459 4FF

EXAMPLE 5

Step 1

A solution of 2-hydroxy-5-nitropyridine (11.2 g, 79.9 mmol) in conc. HCl(57 ml) was warmed to 50° C. and KClO₃ (3.4 g, 27.7 mmol) in water (50ml) was added dropwise at such a rate that the temperature was keptbelow 60° C. During the addition the product began to separate. AfterTLC monitoring indicated complete consumption of starting material themixture was cooled to 0° C. and the product was isolated by vacuumfiltration. The solid was washed with water and dried at 50° C. undervacuum to give the product (12.3 g, 88%) as a solid. ¹HNMR (DMSO-d₆) δ8.68 (d, J=3.2 Hz, 1H), 8.40 (d, J=3.2 Hz, 1H). MS m/e 175 (M+H)⁺.Step 2

To phosphoryl chloride (10.5 g, 68.7 mmol) was added successively, withcooling at 5° C., quinoline (4.4 g, 34.1 mmol) and the product of Step 1(12.0 g, 68.7 mmol). The resultant mixture was heated for 2 hr at 120°C. under N₂. After the reaction was complete as indicated by TLCmonitoring, the reaction mixture was allowed to cool to 100° C., andwater (26 ml) was added. The solution was then cooled in an ice bath andthe product was isolated by vacuum filtration. The solid was washed withwater and dried at 40° C. under vacuum to give the product (12.5 g,94%). ¹HNMR (DMSO-d₆) δ 9.19 (d, J=2.4 Hz, 1H), 8.97 (d, J=2.4 Hz, 1H).Step 3

A flask charged with 3-fluorophenylboronic acid (1.63 g, 11.65 mmol),the product of Step 2 (1.50 g, 7.77 mmol), ethylene glycol dimethylether (18 ml) and potassium phosphate (4.95 g, 23.3 mmol) was purgedwith N₂. PdCl₂(dppf)₂.CH₂Cl₂ (0.26 g, 0.32 mmol) was added. The reactionmixture was heated at 80° C. under N₂ for 2 hr, allowed to cool, andfiltered through celite. The filtrate was extracted with EtOAc (60 ml)was then washed with saturated sodium carbonate (40 ml), water (40 ml),brine (30 ml), dried (Na₂SO₄), filtered and concentrated. The residuewas subjected to flash chromatography (1:5 CH₂Cl₂/hexane) to give theproduct (1.96 g, 100%). ¹HNMR (CDCl₃) δ 9.39 (d, J=2.4 Hz, 1H), 8.62 (d,J=2.4 Hz, 1H), 7.62 (m, 1H), 7.54 (m, 2H), 7.22 (m, 1H). MS m/e 253(M+H)⁺.Step 4

To an ice-cold solution of the product of Step 3 (2.25 g, 8.9 mmol) andnickel chloride hexahydrate (4.23 g, 17.8 mmol) in MeOH (100 ml) wasadded sodium borohydride (1.11 g, 29.5 mmol) in portions. The resultingmixture was stirred at 0-5° C. for 30 min., water (5 ml) was added andthe whole was concentrated. The residue was treated with EtOAc (100 ml)and filtered through celite. The filtrate was dried (MgSO₄), filteredand concentrated to give the product (2.3 g). ¹HNMR (CDCl₃) δ 7.53 (s,1H), 6.97 (m, 1H), 6.84 (m, 2H), 6.63 (s, 1H), 6.53 (m, 1H), 3.90 (s, b,2H).Step 5

To a solution of the product of Step 4 (500 mg, 2.25 mmol) in anhydrouspyridine (6 ml) was added phenyl chloroformate (390 mg, 2.49 mmol)dropwise. The reaction mixture was stirred for 16 hr then evaporated invacuo. The residue was taken up in chloroform (10 ml), and Et₃N (1 ml)and Preparation 1 (722 mg, 3.37 mmol) was added. The mixture was heatedat 65° C. for 3 hr. The residue was allowed to cool, diluted with CH₂Cl₂(50 ml) and washed with sat'd NaHCO₃ (30 ml), water (30 ml), and NaCl(30 ml). The organic layer was dried (MgSO₄), filtered and evaporated.The residue was subjected to flash chromatography (2:98 CH₃OH/CH₂Cl₂) togive the product (530 mg, 51%). ¹H NMR (CDCl₃) δ 8.41 (d, J=2.4 Hz, 1H),8.28 (d, J=2.4 Hz, 1H), 7.50 (m, 1H), 7.42 (m, 2H), 7.10 (m, 1H), 6.61(s, 1H), 4.41 (m, 1H), 4.22 (m, 2H), 2.92 (s, 3H), 2.80 (m, 2H),1.70-1.57 (m, 4H), 1.45 (s, 9H).Step 6

The product of Step 5 (90 mg, 0.194 mmol) was treated with 4NHCl/1,4-dioxane (4 ml) for 16 hr. The reaction mixture was concentratedand the residue was triturated with Et₂O and dried to give the product(85 mg) as a solid. ¹HNMR (CD₃OD) δ 8.92 (d, J=2.4 Hz, 1H), 8.50 (d,J=2.4 Hz, 1H), 7.58 (m, 1H), 7.51 (m, 2H), 7.30 (m, 1H), 4.45 (m, 1H),3.50 (m, 2H), 3.16 (m, 2H), 3.02 (s, 3H), 2.10-1.90 (m, 4H).

Step 7

To a solution of the product of Step 6 (42 mg, 0.096 mmol) and Et₃N (0.2ml) in CH₂Cl₂ (2 ml) was slowly added acetic anhydride (112 mg, 1.10mmol). The reaction mixture was stirred at R.T. for 2 hr. Theconcentrated residue was separated by PTLC (1:20 CH₃OH/CH₂Cl₂) to givethe product (31 mg, 80%). ¹HNMR (CDCl₃) δ 8.44 (d, J=2.4 Hz, 1H), 8.27(d, J=2.4 Hz, 1H), 7.50 (m, 1H), 7.42 (m, 2H), 7.10 (m, 1H), 6.92 (s,1H), 4.75 (m, 1H), 4.50(m, 1H), 3.92 (m, 1H), 3.17 (t, 1H), 2.90 (s,3H), 2.60 (m, 1H), 2.11 (s, 3H), 1.81-1.60 (m, 4H). MS m/e 405 (M+H)⁺.

Use of the appropriate reagents and procedures afforded the followingcompounds: STRUCTURE ¹H NMR MS (M + H)⁺

(CDCl₃) δ 8.44 (d, J = 2.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.49 (m,1H), 7.43 (m, 2H), 7.10 (m, 1H), 6.65 (s, 1H), 4.43 (m, 1H), 3.92 (m,2H), 2.93 (s, 3H), 2.78 (m, 5H), 1.81 (m, 4H). 441 5A

(CDCl₃) δ 8.44 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.50 (m,1H), 7.41 (m, 2H), 7.10 (m, 1H), 6.61 (s, 1H), 4.44 (m, 1H), 3.93 (m,2H), 2.93 (m, 7H), 1.81 (m, 4H), 1.36 (t, 3H). 455 5B

(CDCl₃) δ 8.44 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.50 (m,1H), 7.41 (m, 2H), 7.10 (m, 1H), 6.67 (s, 1H), 4.44 (m, 1H), 3.93 (m,2H), 2.90 (m, 7H), 1.81 (m, 6H), 1.06 (t, 3H). 469 5C

(CDCl₃) δ 8.43 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.51 (m,1H), 7.43 (m, 2H), 7.10 (m, 1H), 6.60 (s, 1H), 4.46 (m, 1H), 3.96 (m,2H), 3.19 (m, 1H), 3.01 (m, 2H), 2.93 (s, 3H), 1.79 (m, 4H), 1.34 (d,6H). 469 5D

(CDCl₃) δ 8.43 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.51 (m,1H), 7.43 (m, 2H), 7.10 (m, 1H), 6.64 (s, 1H), 4.43 (m, 1H), 3.92 (m,2H), 2.93 (m, 5H), 2.27 (m, 1H), 1.81 (m, 4H), 1.16 (m, 2H), 1.00 (m,2H). 467 5E

(CDCl₃) δ 8.44 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.48 (m,1H), 7.40 (m, 2H), 7.10 (m, 1H), 6.92 (s, 1H), 4.76 (m, 1H), 4.50 (m,1H), 3.94 (m, 1H), 3.12 (t, 1H), 2.90 (s, 3H), 2.60 (m, 1H), 2.36 (q,2H), 1.80-1.55 (m, 4H), 1.15 (t, 3H). 419 5F

(CDCl₃) δ 8.43 (d, J = 2.4 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.50 (m,1H), 7.40 (m, 2H), 7.10 (m, 1H), 6.89 (s, 1H), 4.76 (m, 1H), 4.51 (m,1H), 3.32 (m, 1H), 3.12 (m, 1H), 2.90 (s, 3H), 2.64 (m, 1H), 1.89-1.55(m, 5H), 0.98 (m, 2H), 0.77 (m, 2H). 431 5G

(CDCl₃) δ 8.43 (d, J = 2.4 Hz, 1H), 8.27 (m, 2H), 7.10 (m, 1H), 6.78 (s,1H), 4.79 (m, 1H), 4.50 (m, 1H), 3.96 (m, 1H), 3.13 (t, 1H), 2.91 (s,3H), 2.60 (m, 1H), 2.33 (q, 2H), 1.81-1.55 (m, 6H), 0.97 (t, 3H). 433 5H

(CDCl₃) δ 8.43 (d, J = 2.4 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.48 (m,1H), 7.38 (m, 2H), 7.08 (m, 1H), 7.02 (s, 1H), 4.39 (m, 1H), 3.75 (m,2H), 2.90-2.80 (m, 11H), 1.67 (m, 4H). 434 5I

(CDCl₃) δ 8.43 (d, J = 2.4 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.50 (m,1H), 7.43 (m, 2H), 7.08 (m, 1H), 6.69 (s, 1H), 4.41 (m, 1H), 3.75 (m,2H), 3.20 (q, 4H), 2.90 (s, 3H), 2.85 (m, 2H), 1.69 (m, 4H), 1.27 (t,6H). 462 5J

(CDCl₃) δ 8.43 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.49 (m,1H), 7.40 (m, 2H), 7.09 (m, 1H), 6.87 (s, 1H), 4.80 (m, 1H), 4.51 (m,1H), 4.05 (m, 1H), 3.14 (m, 1H), 2.90 (s, 3H), 2.80 (m, 1H), 2.59 (m,1H), 1.82-1.56 (m, 4H), 1.13 (m, 6H). 433 5K

(CDCl₃) δ 8.40 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.29 (m,2H), 6.85 (m, 1H), 6.49 (m, 1H), 4.42 (m, 1H), 4.23 (m, 2H), 2.93 (s,3H), 2.81 (m, 2H), 1.70-1.57 (m, 4H), 1.45 (m, 9H). 481 5L

(CDCl₃) δ 8.44 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.27 (m,2H), 6.84 (m, 1H), 6.73 (s, 1H), 4.41 (m, 1H), 3.92 (m, 2H), 2.93 (s,3H), 2.78 (m, 5H), 1.81 (m, 4H). 459 5M

(CDCl₃) δ 8.43 (m, 1H), 8.28 (m, 1H), 7.28 (m, 2H), 6.84 (m, 1H), 6.54(s, 1H), 4.45 (m, 1H), 3.94 (m, 2H), 2.95 (m, 7H), 1.81 (m, 4H), 1.36(t, 3H). 473 5N

(CDCl₃) δ 8.42 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.27 (m,2H), 6.84 (m, 1H), 6.52 (s, 1H), 4.45 (m, 1H), 3.94 (m, 2H), 2.95 (s,3H), 2.88 (m, 4H), 1.85 (m, 6H), 1.07 (t, 3H). 487 5O

(CDCl₃) δ 8.43 (d, J = 2.4 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.27 (m,2H), 6.84 (m, 1H), 6.58 (s, 1H), 4.45 (m, 1H), 3.94 (m, 2H), 3.19 (m,1H), 3.00 (m, 2H), 2.95 (s, 3H), 1.75 (m, 4H), 1.35 (d, 6H). 487 5P

(CDCl₃) δ 8.44 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.27 (m,2H), 6.84 (m, 1H), 6.60 (s, 1H), 4.41 (m, 1H), 3.92 (m, 2H), 2.95 (m,5H), 2.28 (m, 1H), 1.81 (m, 4H), 1.17 (m, 2H), 1.00 (m, 2H). 485 5Q

EXAMPLE 6

Step 1

A round-bottom flask charged with 3,5-difluorophenylboronic acid (6.60g, 41.8 mmol), 2-amino-5-bromo pyridine (6.00 g, 34.7 mmol), benzene (80ml), and 2M aq. Na₂CO₃ (40 ml) was purged with N₂ for 5 min. Pd(PPh₃)₄(1.20 g, 1.04 mmol) was added and the reaction mixture was heated to100° C. for 16 hr. After cooling, the reaction mixture was poured intocold water (100 ml). The whole was extracted with CH₂Cl₂ (3×150 ml),dried (Na₂SO₄), and filtered. The concentrated residue was subjected toflash column chromatography (1:10 acetone/hexane) to give the product(4.90 g, 69%). ¹H NMR (CDCl₃) δ 8.28 (d, J=2.4 Hz, 1H), 7.63 (dd, J=8.8,2.4 Hz, 1H), 7.01 (m, 2H), 6.76 (m, 1H), 6.58 (d, J=8.4 Hz, 1H), 4.65(s, b, 2H). MS m/e 207 (M+H)⁺.Step 2

To a solution of the product of Step 1 (0.300 g, 1.45 mmol) in anhydrouspyridine (5 ml) was added phenyl chloroformate (0.20 ml, 1.60 mmol)dropwise under argon. The reaction mixture was stirred at R.T. for 16 hrand evaporated in vacuo to give crude the product (0.388 g). ¹H NMR(CDCl₃) δ 8.53 (m, 1H), 8.42 (t, 2H), 8.15 (d, 1H), 7.41 (t, 2H), 7.24(m, 3H), 7.07 (m, 2H), 6.83 (m, 1H) MS m/e 327 (M+H)⁺.Step 3

To a solution of the product of Step 2 (0.200 g, 0.613 mmol) inchloroform (10 ml) was added Preparation 1 (HCl salt) (0.230 g, 0.919mmol) and Et₃N (0.43 ml, 3.06 mmol). The reaction mixture was refluxedfor 16 hr, then allowed to cool and concentrated. Subjection of theresidue to PTLC (1:2 EtOAc/hexane) gave the product (0.062 g, 23%) as asolid. ¹HNMR (CDCl₃) δ 8.40 (s, 1H), 8.16 (d, 1H), 7.85 (m, 1H), 7.27(s, 1H), 7.07 (m, 2H), 6.69 (m, 1H), 4.42 (m, 1H), 4.25 (s, b, 2H), 2.92(s, 3H), 2.82 (m, 2H), 1.67 (m, 4H), 1.47 (s, 9H). MS m/e 447 (M+H)⁺.Step 4.

A mixture of the product of Step 3 (0.205 g, 0.460 mmol) and 4NHCl/1,4-dioxane (5 ml) was stirred at R.T. for 1 hr, then evaporated togive the product (0.137 g, 100%) as a solid. MS m/e 347 (M+H)⁺.

Step 5

To a solution of the product of Step 4 (0.042 g, 0.11 mmol) and iPr₂NEt(0.057 ml, 0.33 mmol) in CH₂Cl₂ (2.0 ml) was slowly added acetylchloride (7.0 μl, 0.1 mmol). The reaction mixture was stirred at R.T.for 16 hr, then concentrated. Subjection of the residue to PTLC (1:10MeOH/CH₂Cl₂) gave the product (0.030 g, 78%) as a solid. ¹HNMR (CDCl₃) δ8.39 (m, 1H), 8.15 (m, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.28 (s, 1H),7.06 (m, 2H), 6.79 (m, 1H), 4.78 (m, 1H), 4.51 (m, 1H), 3.92 (m, 1H),3.18 (m, 1H), 2.91 (s, 3H), 2.62 (m, 1H), 2.12 (s, 3H), 1.78 (m, 2H),1.60 (m, 2H). MS m/e 389 (M+H)⁺. STRUCTURE ¹H NMR MS (M + H)⁺

¹H NMR (DMSO-d₆) 68.44 (1H, s), 8.11 (1H, m), 7.88 (1H, m), 7.55 (2H,m), 7.45 (2H, m), 7.35 (1H, m), 4.39 (1H, m), 3.20 (2H, m), 2.97 (3H,s), 2.49 (3H, s) 2.40 (2H, m), 2.13 (2H, m), 1.76 (2H, m). 325 6A

(CDCl₃) δ 8.40 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.84 (dd,J = 8.8, 2.4 Hz, 1H), 7.29 (s, 1H), 7.07 (m, 2H), 6.80 (m, 1H), 4.44 (m,1H), 3.93 (m, 2H), 2.96 (s, 3H), 2.81 (s, 3H), 2.80 (m, 2H), 1.84 (m,4H) 425 6B

(CDCl₃) δ 8.39 (d, J = 2.4 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.83 (dd,J = 8.8, 2.4 Hz, 1H), 7.30 (s, 1H), 7.06 (m, 2H), 6.79 (m, 1H), 4.79 (m,1H), 4.51 (m, 1H), 3.94 (d, b, 1H), 3.13 (m, 1H), 2.91 (s, 3H), 2.61 (m,1H), 2.37 (q, J = 7.6 Hz, 2H), 1.78 (m, 2H), 1.60 (m, 2H), 1.16 (t, J =7.6 Hz, 3H) 403 6C

(CDCl₃) δ 8.40 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.83 (dd,J = 8.8, 2.4 Hz, 1H), 7.27 (s, 1H), 7.06 (m, 2H), 6.79 (m, 1H), 4.82 (m,1H), 4.51 (m, 1H), 3.97 (d, b, 1H), 3.14 (m, 1H), 2.91 (s, 3H), 2.61 (m,1H), 2.33 (t, J = 6.8 Hz, 2H), 1.90-1.50 (m, 6H), 0.98 (t, J = 7.6 Hz,3H) 417 6D

EXAMPLE 7

Step 1

To a solution of 2-amino-5-bromopyridine (5.00 g, 28.9 mmol) inanhydrous pyridine (50 ml) was added phenyl chloroformate (4.0 ml, 31.8mmol) dropwise under argon. The reaction mixture was stirred for 22 hr,then poured into EtOAc (200 ml). The resultant precipitate wascollected, washed with EtOAc, and dried in vacuo.

To a solution of the crude product was added Preparation 1 (6.19 g, 28.9mmol), Et₃N (12.0 ml, 86.7 mmol) and CHCl₃ (100 ml). The reactionmixture was refluxed for 24 hr, allowed to cool and poured into cold H₂O(˜200 ml). The whole was extracted with CH₂Cl₂ (3×200 ml), dried(Na₂SO₄), filtered and evaporated. The residue was subjected to flashchromatography (1:4 then 1:2 EtOAc/hexane) to give the product as asolid (7.20 g, 60%). ¹H NMR (CDCl₃) δ 8.17 (m, 1H), 7.94 (m, 1H), 7.68(m, 1H), 7.22 (s, 1H), 4.32 (m, 1H), 4.18 (s, b, 2H), 2.83 (s, 3H), 2.74(m, 2H), 1.58 (m, 4H), 1.41 (s, 9H). MS m/e 413 (M+H)⁺.Step 2

A flask charged with 3-fluorophenyl boronic acid (0.537 g, 3.87 mmol),the product of Step 1 (7-1), (0.800 g, 1.94 mmol), Cs₂CO₃ (0.695 g, 2.13mmol), toluene (30 ml) and H₂O (1 ml) was purged with N₂.PdCl₂(dppf)₂.CH₂Cl₂ (0.317 g, 0.387 mmol) was added, and the reactionmixture was refluxed for 1.5 hr, allowed to cool, then poured into coldwater (100 ml). The whole was extracted with CH₂Cl₂ (3×100 ml) and dried(Na₂SO₄). The concentrated residue was subjected to PTLC (1:2acetone/hexane) to give the product (0.382 g, 46%) as a film. ¹H NMR(CDCl₃) δ 8.41 (d, 1H), 8.15 (d, 1H), 7.86 (dd, 1H), 7.42-7.20 (m, 4H),7.05 (m, 1H), 4.42 (m, 1H), 4.33 (s, b, 2H), 2.92 (s, 3H), 2.82 (m, 2H),1.78-1.50 (m, 4H), 1.46 (m, 9H). MS m/e 429 (M+H)⁺.Step 3

Reaction of the product of Step 2 by the method of Example 6, Step 4gave the product. MS m/e 329 (M+H)⁺.

Step 4

Using essentially the same procedure as Example 4, reaction of theproduct of Step 3 with CH₃COCl and Et₃N gave the product. ¹H NMR (CDCl₃)δ 8.42 (d, 1H), 8.13 (m, 1H), 7.87 (m, 1H), 7.45-7.20 (m, 4H), 7.05 (m,1H), 4.78 (m, 1H), 4.51 (m, 1H), 3.92 (m, 1H), 3.18 (m, 1H), 2.91 (s,3H), 2.63 (m, 1H), 2.12 (s, 3H), 1.78 (m, 2H), 1.60 (m, 2H). MS m/e 371(M+H)⁺.

Using appropriate procedures, the following Examples were prepared.STRUCTURE ¹H NMR MS (M + H)⁺

(CDCl₃) δ 8.37 (s, 1H), 8.15 (d, 1H), 7.83 (m, 1H), 7.28 (s, 1H), 7.13(m, 2H), 7.01 (m, 1H), 4.41 (m, 1H), 4.22 (s, b, 2H), 2.91 (s, 3H), 2.80(m, 2H), 1.75-1.50 (m, 4H), 1.46 (s, 9H) 447 7A

(CDCl₃) δ 8.39 (s, 1H), 8.15 (d, 1H), 7.85 (d, 1H), 7.32 (s, b, 1H),7.14 (m, 2H), 7.03 (m, 1H), 4.43 (m, 1H), 3.94 (d, b, 2H), 2.95 (s, 3H),2.81 (s, 3H), 2.78 (m, 2H), 1.84 (m, 4H) 425 7B

(CDCl₃) δ 8.39 (s, 1H), 8.14 (d, 1H), 7.84 (d, 1H), 7.26 (s, 1H), 7.14(m, 2H), 7.00 (m, 1H), 4.78 (d, b, 1H), 4.51 (m, 1H), 3.91 (d, b, 1H),3.18 (m, 1H), 2.91 (s, 3H), 2.62 (m, 1H), 2.12 (s, 3H), 1.78 (m, 2H),1.61 (m, 2H) 389 7C

(CDCl₃) δ 8.39 (s, 1H), 8.15 (d, 1H), 7.85 (m, 1H), 7.27 (s, 1H), 7.14(m, 2H), 7.02 (m, 1H), 4.81 (d, b, 1H), 4.51 (m, 1H), 3.95 (d, b, 1H),3.14 (m, 1H), 2.91 (s, 3H), 2.62 (m, 1H), 2.37 (q, 2H), 1.77 (m, 2H),1.61 (m, 2H), 1.16 (t, 3H) 403 7D

(CDCl₃) δ 8.39 (s, 1H), 8.14 (dd, 1H), 7.85 (m, 1H), 7.26 (s, 1H), 7.12(m, 2H), 7.02 (m, 1H), 4.81 (m, 1H), 4.51 (m, 1H), 3.97 (d, b, 1H), 3.14(m, 1H), 2.91 (s, 3H), 2.61 (m, 1H), 2.33 (t, 2H), 1.90-1.50 (m, 6H),0.98 (t, 3H) 417 7E

(CDCl₃) δ 8.42 (d, 1H), 8.13 (d, 1H), 7.87 (dd, 1H), 7.45-7.20 (m, 4H),7.06 (m, 1H), 4.45 (m, 1H), 3.93 (m, 2H), 3.05 (s, 3H), 2.81 (s, 3H),2.80 (m, 2H), 1.83 (m, 4H) 407 7F

(CDCl₃) δ 8.41 (d, 1H), 8.13 (d, 1H), 7.86 (dd, 1H), 7.45-7.20 (m, 4H),7.05 (m, 1H), 4.81 (m, 1H), 4.52 (m, 1H), 3.95 (m, 1H), 3.13 (m, 1H),2.91 (s, 3H), 2.62 (m, 1H), 2.36 (q, 2H), 1.75 (m, 2H), 1.58 (m, 2H),1.16 (t, 3H) 385 7G

EXAMPLE 8

Step 1

Reaction of 6-2 with Preparation 10 using the procedure of Example 6,Step 3, gave the product. ¹HNMR (CDCl₃) δ 8.38 (d, J=2.0 Hz, 1H), 8.13(d, J=8.8 Hz, 1H), 7.82 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (s, 1H), 7.06 (m,2H), 6.78 (m, 1H), 5.04 (m, 1H), 3.70-3.10 (m, 4H), 2.98 (s, 3H), 2.10(m, 1H), 1.97 (m, 1H), 1.45 (s, 9H). MS m/e 433 (M+H)⁺.Step 2

The product of Step 1 was treated with HCl by the procedure of Example6, Step 4, to give the product. ¹H NMR (CD₃OD) δ 8.63 (m, 2H), 7.85 (d,1H), 7.42 (m, 2H), 7.13 (m, 1H), 4.82 (m, 1H), 4.80-4.40 (m, 4H), 3.22(s, 3H), 2.43 (m, 1H), 2.32 (m, 1H). MS m/e 333 (M+H)⁺.

Step 3

Using the procedure of Example 3, Step 3, the product was synthesized in56% yield as a solid. ¹H NMR (CDCl₃) δ 8.38 (d, 1H), 8.22 (d, 1H), 7.90(m, 1H), 7.26 (s, 1H), 7.06 (m, 2H), 6.83 (m, 1H), 5.15 (m, 1H), 3.67(m, 1H), 3.52 (m, 1H), 3.35 (m, 1H), 3.25 (m, 1H), 3.07 (s, 3H), 2.90(s, 3H), 2.25 (m, 1H), 2.08 (m, 1H). MS m/e 411 (M+H)⁺.

EXAMPLE 9

A mixture of Example 6B (0.030 g, 0.071 mmol), CH₂Cl₂ (5 ml) and mCPBA(57-80%, 0.032 g) was stirred at R.T. for 1.5 hr, then poured into H₂O(10 ml). The whole was extracted with CH₂Cl₂ (3×20 ml), dried (Na₂SO₄),filtered and concentrated. Subjection of the residue to PTLC (1:20CH₃OH/CH₂Cl₂) gave the product (0.0194 mg, 62%) as a solid. ¹H NMR(CDCl₃) δ 9.81 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.37 (d, J=9.2 Hz, 1H),7.49 (dd, J=8.8, 2.0 Hz, 1H), 7.04 (m, 2H), 6.86 (m, 1H), 4.39 (s, b,1H), 3.95 (d, b, 2H), 3.02 (s, 3H), 2.83 (m, 5H), 1.88 (m, 4H). MS m/e441 (M+H)⁺.

EXAMPLE 10

Step 1

A flask charged with 2-amino-5-bromopyrazine (4.00 g, 23.0 mmol),3,5-difluorophenylboronic acid (5.44 g, 34.5 mmol), toluene (150 ml),water (5 ml) and cesium carbonate (8.24 g, 25.3 mmol) was purged withN₂. PdCl₂(dppf).CH₂Cl₂ (0.93 g, 1.15 mmol) was added and the mixture wasrefluxed 2 hr, allowed to cool, then poured into cold water (100 ml).The whole was extracted with CH₂Cl₂ (3×200 ml), dried (Na₂SO₄), andfiltered. The concentrated residue was subjected to flash columnchromatography (1:4 then 1:2 acetone/hexane) to give the product (4.42g, 93%). ¹HNMR (CDCl₃) δ 8.42 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H),7.42 (m, 2H), 6.79 (m, 1H), 4.75 (s, 2H). MS m/e 208 (M+H)⁺.Step 2

To a solution of the product of Step 1 (2.00 g, 9.65 mmol) in anhydrouspyridine (40 ml) was added phenyl chloroformate dropwise under argon.The reaction mixture was stirred for 16 hr, then concentrated. To theresidue was added chloroform (50 ml), followed by Preparation 1 (3.10 g,14.5 mmol) and Et₃N (4.0 ml, 28.9 mmol). The reaction mixture wasrefluxed for 4 hr, then allowed to cool and poured into water. The wholewas extracted with CH₂Cl₂ (3×200 ml) and dried (Na₂SO₄), filtered andconcentrated. Crystallization of the residue (acetone/hexane) gave theproduct (2.52 g, 58%). The mother liquor was concentrated and subjectedto flash chromatography (1:5 acetone/hexane) to afford additionalproduct (0.943 g, total 80%). ¹H NMR (CDCl₃) δ 9.45 (d, J=1.6 Hz, 1H),8.55 (d, J=1.2 Hz, 1H), 7.51 (m, 2H), 7.17 (s, 1H), 6.85 (m, 1H), 4.43(m, 1H), 4.24 (m, 2H), 2.95 (s, 3H), 2.82 (m, 2H), 1.63 (m, 4H), 1.47(s, 9H). MS m/e 448 (M+H)⁺.Step 3

The product of Step 2 (2.50 g, 5.59 mmol) was treated with 4MHCl/1,4-dioxane (30 ml) by the procedure of Example 6, Step 4 to affordthe product. ¹H NMR (CD₃OD) δ 9.19 (s, b, 1H), 8.79 (s, b, 1H), 7.66 (m,2H), 7.03 (m, 1H), 4.42-3.49 (m, 5H), 3.16 (m, 2H), 3.04 (s, 3H),2.20-1.95 (m, 4H). MS m/e 348 (M+H)⁺.

Step 4

To a mixture of the product of Step 3 (2.15 g, 5.59 mmol), and Et₃N (3.9ml, 28.0 mmol) in CH₂Cl₂ (50 ml) was added acetic anhydride (0.58 ml,6.15 mmol). The reaction mixture was stirred for 16 hr, then poured intowater (100 ml). The whole was extracted with CH₂Cl₂ (3×200 ml), dried(Na₂SO₄), filtered, and evaporated. The residue was subjected to flashchromatography (gradient 1:100-5:95 MeOH/CH₂Cl₂) to give the product(1.71 g, 78%). ¹H NMR (CDCl₃) δ 9.44 (d, J=1.2 Hz, 1H), 8.55 (d, J=1.6Hz, 1H), 7.51 (m, 2H), 7.23 (s, 1H), 6.84 (m, 1H), 4.79 (m, 1H), 4.53(m, 1H), 3.91 (m, 1H), 3.20 (m, 1H), 2.94 (s, 3H), 2.63 (m, 1H), 2.12(s, 3H), 1.86-1.55 (m, 4H). MS m/e 390 (M+H)⁺.

Use of the appropriate procedures afforded the following compounds:STRUCTURE ¹H NMR MS (M + H)⁺

(CDCl₃) δ 9.44 (bs, 1H), 8.55 (bs, 1H), 7.52 (m, 2H), 7.22 (s, 1H), 6.85(m, 1H), 4.79 (m, 1H), 4.53 (m, 1H), 3.91 (m, 1H), 3.20 (m, 1H), 2.94(s, 3H), 2.63 (m, 1H), 2.37 (m, 2H), 1.86-1.55 (m, 4H), 1.16 (m, 3H).404 10A

(CDCl₃) δ 9.45 (bs, 1H), 8.56 (bs, 1H), 7.52 (m, 2H), 7.19 (s, 1H), 6.85(m, 1H), 4.81 (m, 1H), 4.53 (m, 1H), 3.98 (m, 1H), 3.15 (m, 1H), 2.94(s, 3H), 2.62 (m, 1H), 2.33 (m, 2H), 1.83-1.56 (m, 6H), 0.98 (m, 3H).418 10B

(CDCl₃) δ 9.45 (bs, 1H), 8.56 (bs, 1H), 7.52 (m, 2H), 7.26 (s, 1H), 6.85(t, 1H), 4.82 (b, 1H), 453 (m, 1H), 4.10 (b, 1H), 3.15 (t, 1H), 2.93 (m,4H), 2.62 (t, 1H), 1.90-1.50 (m, 12H). 444 10C

(CDCl₃) δ 9.45 (d, J = 1.2 Hz, 1H), 8.56 (d, J = 1.2 Hz, 1H), 7.51 (m,2H), 7.21 (s, 1H), 6.84 (m, 1H), 4.83 (m, 1H), 4.54 (m, 1H), 4.05 (m,1H), 3.16 (m, 1H), 2.94 (s, 3H), 2.84 (m, 1H), 2.62 (m, 1H), 1.82 (m,2H), 1.58 (m, 2H), 1.14 (m, 6H) 418 10D

(CDCl₃) δ 9.45 (d, J = 1.2 Hz, 1H), 8.56 (d, J = 1.2 Hz, 1H), 7.51 (m,2H), 7.22 (s, 1H), 6.84 (m, 1H), 4.77 (m, 1H), 4.56 (m, 1H), 4.38 (m,1H), 3.22 (m, 1H), 2.94 (s, 3H), 2.67 (m, 1H), 1.90-1.55 (m, 5H), 1.00(m, 2H), 0.78 (m, 2H) 416 10E

(CDCl₃) δ 9.43 (d, J = 1.6 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.51 (m,2H), 7.28 (s, 1H), 6.84 (m, 1H), 4.76 (m, 1H), 4.56 (m, 1H), 4.11 (q,2H), 4.02 (m, 1H), 3.43 (s, 3H), 3.17 (m, 1H), 2.93 (s, 3H), 2.68 (m,1H), 1.95-1.57 (m, 4H) 420 10F

(CDCl₃) δ 9.45 (d, J = 1.6 Hz, 1H), 8.55 (d, J = 1.2 Hz, 1H), 7.51 (m,2H), 7.24 (s, 1H), 6.84 (m, 1H), 4.82 (m, 1H), 4.53 (m, 1H), 4.03 (m,1H), 3.15 (m, 1H), 2.93 (s, 3H), 2.61 (m, 1H), 2.49 (m, 1H), 1.95-1.20(m, 14 H) 458 10G

(CDCl₃) δ 9.44 (d, J = 1.6 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.51 (m,2H), 7.23 (s, 1H), 6.84 (m, 1H), 4.82 (m, 1H), 4.53 (m, 1H), 4.00 (m,1H), 3.15 (m, 1H), 2.93 (s, 3H), 2.61 (m, 1H), 2.23 (m, 2H), 2.14 (m,1H), 1.90-1.50 (m, 4H), 0.98 (m, 6H) 432 10H

(CDCl₃) δ 9.44 (s, 1H), 8.55 (s, 1H), 7.51 (m, 2H), 7.25 (s, 1H), 6.84(m, 1H), 4.85 (m, 1H), 4.53 (m, 1H), 4.05 (m, 1H), 3.17 (m, 1H), 2.93(s, 3H), 2.61 (m, 1H), 2.28 (q, 2H), 1.90-1.50 (m, 4H), 1.04 (m, 9H) 44610I

(CDCl₃) δ 9.42 (d, J = 1.6 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 7.49 (m,2H), 7.32 (s, 1H), 6.83 (m, 1H), 4.82 (m, 1H), 4.57 (m, 1H), 3.97 (m,1H), 3.18 (m, 1H), 2.93 (s, 3H), 2.62 (m, 1H), 2.30 (m, 2H), 1.85-1.50(m, 4H), 1.03 (m, 1H), 0.57 (m, 2H), 0.17 (m, 2H) 430 10J

(CDCl₃) δ 9.45 (s, 1H), 8.55 (s, 1H), 7.51 (m, 2H), 7.24 (s, 1H), 6.83(m, 1H), 4.55 (m, 3H), 2.93 (m, 3H), 2.84 (m, 2H), 1.90-1.50 (m, 4H),1.29 (s, 9H) 432 10K

(CDCl₃) δ 9.44 (d, J = 1.6 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.49 (m,2H), 7.45 (m, 1H), 7.31 (m, 1H), 7.28 (s, 1H), 7.05 (m, 1H), 6.84 (m,1H), 4.62 (m, 3H), 3.08 (m, 2H), 2.97 (s, 3H), 1.90-1.60 (m, 4H) 458 10L

(CDCl₃) δ 9.44 (d, J = 1.6 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.52 (m,2H), 7.42 (m, 5H), 7.26 (s, 1H), 6.85 (m, 1H), 4.90 (bs, 1H), 4.78 (m,1H), 3.90 (bs, 1H), 3.15 (m, b, 1H), 2.97 (s, 3H), 2.87 (bs, 1H),2.90-1.50 (m, b, 4H) 452 10M

(CDCl₃) δ 9.45 (d, J = 1.6 Hz, 1H), 8.55 (d, J = 1.2 Hz, 1H), 7.51 (m,2H), 7.22 (s, 1H), 6.85 (m, 1H), 4.82 (b, 1H), 4.58 (m, 1H), 4.07 (b,1H), 3.17 (m, 1H), 2.94 (s, 3H), 2.75 (m, 1H), 2.61 (m, 1H), 1.90-1.50(m, 5H), 1.38 (m, 3H), 1.12 (m, 3H), 0.92 (m, 3H) 446 10N

(CDCl₃) δ 9.44 (d, J = 1.2 Hz, 1H), 8.55 (s, 1H), 7.51 (m, 2H), 7.22 (s,1H), 6.85 (m, 1H), 4.78 (m, 1H), 4.52 (m, 1H), 3.81 (m, 1H), 3.27 (m,1H), 3.08 (m, 1H), 2.92 (s, 3H), 2.65 (m, 1H), 2.34 (m, 2H), 2.16 (m,2H), 2.10-1.40 (m, 6H) 430 10O

(CDCl₃) δ 9.44 (s, 1H), 8.55 (s, 1H), 7.51 (m, 2H), 7.28 (s, 1H), 6.83(m, 1H), 4.92 (b, 1H), 4.55 (m, 1H), 4.15 (b, 1H), 3.17 (m, 1H), 2.92(s, 3H), 2.62 (m, 1H), 2.54 (m, 1H), 1.90-1.40 (m, 8H), 0.87 (m, 6H) 44610P

(CDCl₃) δ 9.42 (d, J = 1.6 Hz, 1H), 8.68 (bs, 2H), 8.55 (d, J =1.6 Hz,1H), 7.76 (m, 1H), 7.51 (m, 2H), 7.38 (m, 1H), 7.28 (s, 1H), 6.83 (m,1H), 4.90 (bs, 1H), 4.80 (m, 1H), 3.85 (bs, 1H), 3.25 (bs, 1H), 2.97 (s,3H), 2.90 (bs, 1H), 2.00-1.50 (m, b, 4H) 453 10Q

¹HNMR (CDCl₃) δ 9.44 (d, 1H), 8.62 (bs., 1H), 8.55 (d, 1H), 7.51 (m,2H), 6.84 (m, 1H), 5.06 (m, 1H), 3.70-3.10 (m, 4H), 3.01 (s, 3H), 2.12(m, 1H), 1.98 (m, 1H), 1.47 (s, 9H). 434 10R

(CDCl₃) δ 9.42 (s, 1H), 8.58 (s, 1H), 7.52 (m, 2H), 7.24 (s, 1H), 6.85(m, 1H), 5.16 (m, 1H), 3.67 (m, 1H), 3.51 (m, 1H), 3.37 (m, 1H), 3.25(m, 1H), 3.09 (s, 3H), 2.89 (s, 3H), 2.26 (m, 1H), 2.10 (m, 1H) 412 10S

(CDCl₃) δ 9.42 (s, 1H), 8.56 (m, 1H), 7.50 (m, 2H), 7.32 (d, 1H), 6.84(m, 1H), 5.11 (m, 1H), 3.82-3.28 (m, 4H), 3.01 (d, 3H), 2.32-1.90 (m,5H) 376 10T

(CDCl₃) δ 9.42 (s, 1H), 8.56 (m, 1H), 7.50 (m, 2H), 7.27 (d, 1H), 6.84(m, 1H), 5.11 (m, 1H), 4.87-3.25 (m, 4H), 3.02 (d, 3H), 2.40-1.90 (m,4H), 1.15 (m, 3H) 390 10U

(CDCl₃) δ 9.43 (s, 1H), 8.57 (bs, 1H), 7.51 (m, 2H), 2.27 (s, 1H), 6.83(m, 1H), 5.09 (m, 1H), 3.90-3.30 (m, 4H), 3.03 (d, 3H), 2.65 (m, 1H),2.30-1.90 (m, 2H), 1.14 (m, 6H) 404 10V

(CDCl₃) δ 9.44 (s, 1H), 8.56 (s, 1H), 7.52 (m, 2H), 7.25 (s, 1H), 6.85(m, 1H), 4.43 (m, 1H), 3.94 (b, 2H), 2.98 (s, 3H), 2.81 (m, 5H), 1.84(m, 4H) 426 10W

(CDCl₃) δ 9.42 (s, 1H), 8.58 (s, 1H), 7.71 (m, 2H), 7.42 (m, 1H), 7.19(s, 1H), 7.10 (m, 1H), 4.42 (m, 1H), 3.92 (m, 2H), 2.97 (s, 3H), 2.80(s, 5H), 1.83 (m, 4H). 408 10X

(CDCl₃) δ 9.42 (d, J = 1.6 Hz, 1H), 8.57 (s, 1H), 7.72 (m, 2H), 7.42 (m,1H), 7.24 (s, 1H), 7.08 (m, 1H), 4.79 (m, 1H), 4.53 (m, 1H), 3.91 (m,1H), 3.19 (m, 1H), 2.93 (s, 3H), 2.62 (m, 1H), 2.12 (s, 3H), 1.90-1.50(M, 4H) 372 10Y

(CDCl₃) δ 9.44 (d, J = 1.6 Hz, 1H), 8.57 (d, J = 1.6 Hz, 1H), 7.71 (m,2H), 7.46 (m, 1H), 7.25 (s, 1H), 7.10 (m, 1H), 4.90 (b, 1H), 4.53 (m,1H), 3.95 (b, 1H), 3.14 (m, 1H), 2.93 (s, 3H), 2.61 (m, 1H), 2.37 (q,2H), 1.90-1.50 (m, 4H), 1.16 (t, 3H) 386 10Z

(CDCl₃) δ 9.44 (d, J = 1.6 Hz, 1H), 8.58 (d, J = 1.2 Hz, 1H), 7.71 (m,2H), 7.43 (m, 1H), 7.19 (s, 1H), 7.11 (m, 1H), 4.93 (b, 1H), 4.58 (m,1H), 4.08 (b, 1H), 3.18 (m, 1H), 2.94 (s, 3H), 2.82 (m, 1H), 2.63 (m,1H), 1.90-1.50 (m, 4H), 1.14 (m, 6H) 400 10AA

(CDCl₃) δ 9.45 (s, 1H), 8.59 (s, 1H), 7.72 (m, 2H), 7.45 (m, 1H), 7.20(s, 1H), 7.11 (m, 1H), 4.78 (m, 1H), 4.58 (m, 1H), 4.37 (b, 1H), 3.24(m, 1H), 2.95 (s, 3H), 2.88 (m, 1H), 1.90-1.50 (m, 5H), 0.99 (m, 2H),0.78 (m, 2H) 398 10BB

(CDCl₃) δ 9.48 (d, J = 1.6 Hz, 1H), 8.72 (d, J = 1.6 Hz, 1H), 7.79 (m,1H), 7.21 (s, 1H), 7.15 (m, 1H), 7.07 (m, 1H), 4.81 (b, 1H), 4.57 (m,1H), 3.93 (b, 1H), 3.21 (t, 1H), 2.94 (s, 3H), 2.63 (t, 1H), 2.12 (s,3H), 1.90-1.50 (m, 4H) 390 10CC

(CDCl₃) δ 9.47 (d, J = 1.6 Hz, 1H), 8.71 (m, 1H), 7.78 (m, 1H), 7.27 (s,1H), 7.15 (m, 1H), 7.07 (m, 1H), 4.81 (b, 1H), 4.57 (m, 1H), 3.95 (b,1H), 3.15 (t, 1H), 2.93 (s, 3H), 2.63 (t, 1H), 2.37 (q, 2H), 1.90-1.50(m, 4H), 1.16 (t, 3H) 404 10DD

(CDCl₃) δ 9.48 (d, J = 1.6 Hz, 1H), 8.72 (m, 1H), 7.78 (m, 1H), 7.23 (s,1H), 7.15 (m, 1H), 7.07 (m, 1H), 4.82 (b, 1H), 4.55 (m, 1H), 4.04 (b,1H), 3.17 (b, 1H), 2.94 (s, 3H), 2.82 (m, 1H), 2.62 (b, 1H), 1.90-1.50(m, 4H), 1.15 (m, 6H) 418 10EE

(CDCl₃) δ 9.48 (d, J = 1.6 Hz, 1H), 8.71 (m, 1H), 7.78 (m, 1H), 7.31 (s,1H), 7.15 (m, 1H), 7.07 (m, 1H), 4.78 (b, 1H), 4.55 (m, 1H), 4.35 (b,1H), 3.15 (b, 1H), 2.94 (s, 3H), 2.65 (b, 1H), 1.90-1.50 (m, 5H), 0.98(m, 2H), 0.77 (m, 2H) 416 10FF

(CDCl₃) δ 9.48 (d, J = 1.2 Hz, 1H), 8.70 (m, 1H), 7.78 (m, 1H), 7.31 (s,1H), 7.15 (m, 1H), 7.07 (m, 1H), 4.81 (b, 1H), 4.55 (m, 1H), 4.09 (b,1H), 3.15 (b, 1H), 2.93 (s, 3H), 2.87 (m, 1H), 2.63 (b, 1H), 1.90-1.50(m, 12H). 444 10GG

(CDCl₃) δ 9.43 (d, J = 1.2 Hz, 1H), 8.57 (d, J = 1.2 Hz, 1H), 7.97 (d, J= 1.6 Hz, 1H), 7.83 (m, 1H), 7.40 (m, 2H), 7.22 (s, 1H), 4.78 (m, 1H),4.53 (m, 1H), 3.90 (m, 1H), 3.19 (m, 1H), 2.93 (s, 3H), 2.62 (m, 1H),2.12 (s, 3H), 1.79 (m, 2H), 1.59 (m, 2H) 388 10HH

(CDCl₃) δ 9.43 (d, J = 1.6 Hz, 1H), 8.57 (d, J = 1.6 Hz, 1H), 7.97 (m,1H), 7.85 (m, 1H), 7.40 (m, 2H), 7.23 (s, 1H), 4.81 (m, 1H), 4.55 (m,1H), 3.97 (b, 1H), 3.15 (b, 1H), 2.93 (s, 3H), 2.64 (b, 1H), 2.37 (q,2H), 1.90-1.50 (m, 4H), 1.16 (t, 3H) 402 10II

(CDCl₃) δ 9.42 (d, J = 1.6 Hz, 1H), 8.56 (d, J = 2.0 Hz, 1H), 7.95 (m,1H), 7.81 (m, 1H), 7.39 (m, 2H), 7.21 (s, 1H), 4.81 (b, 1H), 4.55 (m,1H), 4.05 (b, 1H), 3.17 (b, 1H), 2.92 (s, 3H), 2.81 (m, 1H), 2.61 (b,1H), 1.78 (m, 2H), 1.59 (m, 2H), 1.12 (m, 6H) 416 10JJ

(CDCl₃) δ 9.44 (d, J = 1.2 Hz, 1H), 8.57 (d, J = 1.2 Hz, 1H), 7.97 (m,1H), 7.82 (m, 1H), 7.39 (m, 2H), 7.22 (s, 1H), 4.78 (m, 1H), 4.55 (m,1H), 4.35 (m, 1H), 3.23 (m, 1H), 2.94 (s, 3H), 2.86 (m, 1H), 1.90-1.50(m, 5H), 0.99 (m, 2H), 0.78 (m, 2H) 414 10KK

(CDCl₃) δ 9.46 (s, 1H), 8.64 (s, 1H), 8.24 (s, 1H), 8.14 (d, 1H), 7.63(m, 2H), 7.20 (s, 1H), 4.48 (m, 1H), 3.97 (b, 2H), 2.98 (m, 7H), 1.81(m, 4H), 1.37 (t, 3H) 458 10LL

(CDCl₃) δ 9.46 (s, 1H), 8.64 (s, 1H), 8.24 (s, 1H), 8.14 (d, 1H), 7.61(m, 2H), 7.21 (s, 1H), 4.45 (m, 1H), 3.93 (b, 2H), 2.98 (m, 5H), 2.28(m, 1H), 1.82 (m, 4H), 1.19 (m, 2H), 0.99 (m, 2H) 484 10MM

(CDCl₃) δ 9.48 (s, 1H), 8.63 (s, 1H), 8.24 (s, 1H), 8.17 (d, 1H), 7.63(m, 2H), 7.24 (s, 1H), 4.79 (b, 1H), 4.57 (m, 1H), 3.92 (b, 1H), 3.12(t, 1H), 2.95 (s, 3H), 2.63 (t, 1H), 2.13 (s, 3H), 1.90 (m, 2H), 1.82(m, 2H) 422 10NN

(CDCl₃) δ 9.47 (s, 1H), 8.63 (s, 1H), 8.24 (s, 1H), 8.17 (d, 1H), 7.63(m, 2H), 7.21 (s, 1H), 4.83 (b, 1H), 4.55 (m, 1H), 3.98 (b, 1H), 3.18(t, 1H), 2.94 (s, 3H), 2.63 (t, 1H), 2.38 (q, 2H), 1.90-1.50 (m, 4H),1.16 (t, 3H) 436 10OO

(CDCl₃) δ 9.47 (s, 1H), 8.63 (s, 1H), 8.24 (s, 1H), 8.15 (d, 1H), 7.62(m, 2H), 7.22 (s, 1H), 4.83 (b, 1H), 4.58 (m, 1H), 4.05 (b, 1H), 3.19(t, 1H), 2.94 (s, 3H), 2.82 (m, 1H) 2.63 (b, 1H), 1.90-1.50 (m, 4H),1.14 (m, 6H) 450 10PP

(CDCl₃) δ 9.48 (s, 1H), 8.63 (s, 1H), 8.24 (s, 1H), 8.15 (d, 1H), 7.62(m, 2H), 7.22 (s, 1H), 4.79 (b, 1H), 4.58 (m, 1H), 4.37 (b, 1H), 3.22(b, 1H), 2.95 (s, 3H), 2.67 (b, 1H), 2.90-1.50 (m, 5H), 0.99 (m, 2H),0.78 (m, 2H) 448 10QQ

(CDCl₃) δ 9.46 (d, J = 1.2 Hz, 1H), 8.71 (bs, 2H), 8.63 (d, J =1.2 Hz,1H), 8.24 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H),7.67 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.39 (m, b, 1H),7.29 (s, 1H), 4.90 (bs, 1H), 4.62 (m, 1H), 3.83 (bs, 1H), 3.23 (bs, 1H),2.99 (s, 3H), 2.90 (bs, 1H), 1.90-1.50 (m, 4H) 485 10RR

EXAMPLE 11

Step 1

Reaction of 2-amino-5-bromopyrazine and Preparation 11 by the procedureof Example 10, Step 2 gave the product. ¹HNMR (CDCl₃) δ9.18 (d, J=1.2Hz, 1H), 8.26 (d, J=1.2 Hz, 1H), 7.11 (s, 1H), 4.42 (m, 1H), 3.93 (m,2H), 2.95 (s, 3H), 2.79 (m, 5H), 1.81 (m, 4H). MS m/e 394 (M+H)⁺.

Step 2.

A flask charged with 11-1 (0.090 g, 0.23 mmol),2,5-difluorophenylboronic acid (0.044 g, 0.28 mmol), toluene (10 ml),water (0.3 ml) and cesium carbonate (0.082 g, 0.25 mmol) was purged withN₂. PdCl₂(dppf)₂CH₂Cl₂ (0.015 g, 0.019 mmol) was added and the reactionmixture was refluxed for 3 hr, allowed to cool, and filtered. Theconcentrated filtrate was subjected to PTLC (1:1 acetone/hexane) to givethe product (0.046 g, 47%). ¹H NMR (CDCl₃) δ 9.47 (d, J=1.6 Hz, 1H),8.72 (m, 1H), 7.78 (m, 1H), 7.22 (s, 1H), 7.15 (m, 1H), 7.06 (m, 1H),4.48 (m, 1H), 3.95 (m, 2H), 2.98 (s, 3H), 2.83 (m, 5H), 1.86 (m, 4H). MSm/e 426 (M+H)⁺.

Use of the appropriate boronic acid and essentially the same procedureafforded the following compounds: STRUCTURE ¹H NMR MS (M + H)⁺

(CDCl₃) δ 9.46 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 8.20 (m, 1H), 7.69(m, 1H), 7.60 (m, 1H), 7.22 (m, 1H), 4.44 (m, 1H), 3.95 (m, 2H), 2.98(s, 3H), 2.81 (m, 5H), 1.83 (m, 4H). 415 11A

(CDCl₃) δ 9.43 (s, 1H), 8.59 (s, 1H), 7.80 (s, 1H), 7.75 (d, 1H), 7.37(1, 1H) 7.25 (d, 1H), 7.16 (s, 1H), 4.50 (m, 1H), 3.95 (b, 2H), 2.97 (s,3H), 2.82 (m, 5H), 2.44 (s, 3H), 1.84 (m, 4H) 404 11B

(CDCl₃) δ 9.42 (d, J = 1.6 Hz, 1H), 8.59 (s, 1H), 7.52 (m, 2H), 7.39 (t,1H), 7.16 (s, 1H), 6.97 (m, 1H), 4.48 (m, 1H), 3.94 (b, 2H), 3.89 (s,3H), 2.97 (s, 3H), 2.81 (m, 5H), 1.84 (m, 4H) 420 11C

(CDCl₃) δ 9.47 (s, 1H). 8.64 (s, 1H), 8.24 (s, 1H), 8.14 (d, 1H), 7.63(m, 2H), 7.26 (s, 1H), 4.49 (bs, 1H), 3.94 (b, 2H), 2.98 (s, 3H), 2.81(bs, 5H), 1.85 (bs, 4H) 458 11D

(CDCl₃) δ 9.42 (s, 1H), 8.60 (s, 1H), 7.98 (s, 1H), 7.84 (m, 1H), 7.40(m, 2H), 7.19 (s, 1H), 4.42 (m, 1H), 3.90 (m, 2H), 2.97 (s, 3H), 2.81(m, 5H), 1.84 (m, 4H). 424 11E

EXAMPLE 12

Step 1

Reaction of 3-fluorophenylboronic acid with 2-bromo-5-nitrothiophene byessentially the procedure of Example 1, Step 1 gave the product. ¹H NMR(CDCl₃, 400 MHz) δ 7.91 (1H, m), 7.42 (2H, m), 7.32 (1H, m), 7.25 (1H,m), 7.14 (1H, m).Step 2

Reaction of the product of Step 1 with NiCl₂.6H₂O and NaBH₄ byessentially the procedure of Example 2, Step 2 gave the product. ¹H NMR(CDCl₃, 400 MHz) δ 7.25 (2H, m), 7.14 (1H, m), 6.48 (1H, d, J=2 Hz),6.85 (1H, m), 6.15 (1H, d, J=2 Hz), 3.87 (2H, b).Step 3

Reaction of the product of Step 2 with N,N′-disuccinimidyl carbonate andPreparation 1 by the procedure of Example 2, Step 3 gave the product. ¹HNMR (CDCl₃, 400 MHz) δ 7.25 (3H, m), 7.06 (1H, m), 7.05 (1H, d, J=4 Hz),6.89 (1H, m), 6.50 (1H, d, J=4 Hz), 4.44 (1H, m), 4.22 (2H, m), 2.86(3H, s), 2.79 (2H, m), 1.60 (4H, m) 1.47 (9H, s). MS m/e 434 (M+H)⁺.Step 4

Reaction of the product of Step 3 with HCl by essentially the procedureof Example 6, Step 4 gave the product. ¹H NMR (CD₃OD, 400 MHz) δ7.36-7.24 (4H, m), 6.90 (1H, m), 6.73 (1H, m), 4.37 (1H, m), 3.50 (2H,m), 3.13 (2H, m), 2.96 (3H, s), 2.09-1.91 (4H, m).

Step 5

Reaction of the product of Step 4 with methanesulfonyl chloride byessentially the procedure of Example 3, Step 3 gave the product. ¹H NMR(CDCl₃, 400 MHz) δ 7.45 (1H, s), 7.29 (3H, m), 7.05 (1H, d, J=4 Hz),6.88 (1H, m), 6.54 (1H, d, J=4 Hz), 4.40 (1H, m), 3.86 (2H, m), 2.87(3H, s), 2.74 (3H, s), 2.68 (2H, m), 1.76 (4H, m). MS m/e 412 (M+H)⁺.

Use of the appropriate reagents and procedures afforded the followingcompounds. STRUCTURE ¹H NMR MS (M + H)⁺

430 12A

444 12B

376 12D

12D (CDCl₃) δ 7.46(1H, s), 7.28(3H, m), 7.03(1H, s), 6.86(1H, m),6.51(1H, s), 4.74(1H, m), 4.53 (1H, m), 3.85(1H, m), 3.14(1H, m),2.86(3H, s), 2.58(1H, m), 2.10(3H, s), 1.78(2H, m), 1.58 (2H, m) 376

12E (CDCl₃) δ 7.63(1H, s), 7.29(3H, m), 7.03(1H, d, J=4 Hz), 6.87 (1H,m), 6.49(1H, d, J=4 Hz), 4.70(1H, m), 4.52(1H, m), 4.30 (1H, m),3.15(1H, m), 2.85(3H, s), 2.61(1H, m), 1.72(3H, m), 1.58(2H, m),0.95(2H, m), 0.74 (2H, m). 402

12F (CDCl₃) δ 8.66(2H, m), 7.75(1H, d, J=7.6 Hz), 7.56(1H, s), 7.38 (1H,m), 7.28(3H, m), 7.07(1H, d, J=4 Hz), 6.87(1H, m),6.49 (1H, d, J=4 Hz),4.87(1H, m), 4.57(1H, m), 3.78(1H, m), 3.17 (1H, m), 2.88(3H, s),2.84(1H, m), 1.81-1.56(4H, m). 439

12G (CDCl₃) δ 7.68(s, 1H), 7.03(m, 3H) 6.61(m, 1H), 6.50(m, 1H), 4.75(m,1H), 4.50(m, 1H), 3.89 (m, 1H), 3.15(m, 1H), 2.87(s, 3H), 2.59(m, 1H),2.10(s, 3H), 1.75(m, 2H), 1.58(m, 2H). 394

12H (CDCl₃) δ 7.46(s, 1H), 7.04(m, 3H), 6.62(m, 1H), 6.50(m, 1H),4.77(m, 1H), 4.51(m, 1H), 3.94 (m, 1H), 3.09(m, 1H), 2.87(s, 3H),2.59(m, 1H), 2.36(q, J=7.6 Hz, 2H), 1.75(m, 2H), 1.57 (m, 2H), 1.15(t,J=7.6 Hz, 3H). 408

12I (CDCl₃) δ 7.33(s, 1H), 7.03(m, 3H), 6.63(m, 1H), 6.50(m, 1H),4.78(m, 1H), 4.52(m, 1H), 3.95 (m, 1H), 3.11(m, 1H), 2.87(s, 3H),2.58(m, 1H), 2.33(m, 2H), 1.4-1.8(m, 6H), 0.97(t, J=Hz, 3H). 422

12J CDCl₃) δ 7.27(s, 1H), 7.04(m, 3H), 6.63(m, 1H), 6.50(m, 1H), 4.79(m,1H), 4.54(m, 1H), 4.02 (m, 1H), 3.13(m, 1H), 2.88(s, 3H), 2.82(m, 1H),2.58(m, 1H), 1.75(m, 2H), 1.56(m, 2H), 1.14 (m, 6H). 422

12K (CDCl₃) δ 7.44(b, 1H), 7.05(m, 6.63(m, 1H), 6.49(m, 1H), 4.74(m,1H), 4.54(m, 1H), 4.32 (m, 1H), 3.18(m, 1H), 2.87(s, 3H), 2.63(m, 1H),1.5-1.9(m, 5H), 0.97(m, 2H), 0.78(m, 2H). 420

12L (CDCl₃) δ 7.26(s, 1H), 7.04(m, 3H), 6.63(m, 1H), 6.50(m, 1H),4.73(m, 1H), 4.54(m, 1H), 4.11 (m, 2H), 3.97(m, 1H), 3.43(s, 3H),3.10(m, 1H), 2.88(s, 3H), 2.64(m, 1H), 1.77(m, 2H), 1.60 (m, 2H). 424

12M (CDCl₃) δ 7.22(m, 1H), 7.04(m, 3H), 6.64(m, 1H), 6.52(m, 1H),4.45(m, 1H), 3.92(m, 2H), 2.90 (s, 3H), 2.84(m, 4H), 1.80(m, 6H),1.06(t, J=7.4 Hz, 3H). 458

12N (CDCl₃) δ 7.23(m, 1H), 7.04(m, 3H), 6.63(m, 1H), 6.52(m, 1H),4.47(m, 1H), 3.94(m, 2H), 3.19 (m, 1H), 2.96(m, 2H), 2.90(s, 3H),1.74(m, 4H), 1.33(d, J=7.2 Hz, 6H). 458

EXAMPLE 13

Step 1

To an ice-cold solution of 3-fluorobenzoyl chloride (2.0 g, 13 mmol) inpyridine (100 ml) was added thiosemicarbazide (0.96 g, 11 mmol) and thereaction mixture was allowed to warm to R.T. After stirring overnight,the pyridine was evaporated, the residue was taken up in water, and theprecipitate was collected, washed with water, and air-dried to give theproduct (0.85 g, 32%). MS m/e 214 (M+H)⁺.Step 2

To a solution of the product of Step 1 (500 mg, 2.34 mmol,) in toluene(10 ml) was added methanesulfonic acid (0.34 g, 3.5 mmol) dropwise. Thereaction mixture was refluxed for 4 hr, cooled, and the precipitate wascollected, washed with ether, and dried. The solid was then taken up inwater, the solution was basified with ammonia to pH 8, and theprecipitate was collected, washed with water, and dried to give theproduct (206 mg, 46%). MS m/e 196 (M+H)⁺.Step 3

To a solution of the product of Step 2 (50 mg, 0.26 mmol) in CH₂Cl₂ (5ml) was added Et₃N (0.1 ml, 0.8 mmol) followed by 4-nitrophenylchloroformate (52 mg, 0.26 mmol). The reaction mixture was stirred for 1hr, then Preparation 1 (55 mg, 0.26 mmol) was added, and the reactionmixture was stirred overnight. CH₂Cl₂ (10 ml) was added and the mixturewas washed with 1N NaOH (3×), sat'd NaCl, dried (Na₂SO₄), filtered andevaporated. The residue was subjected to PTLC (5:95 MeOH/CH₂Cl₂) to givethe product (48 mg, 42%). ¹H NMR (CDCl₃, 400 MHz) δ 11.33 (1H, b), 7.63(2H, m), 7.41 (1H, m), 7.16 (1H, m), 4.50 (1H, m), 4.23 (2H, b), 3.14(3H, s), 2.79 (2H, b), 1.75 (4H, m), 1.46 (9H, s). MS m/e 436 (M+H)⁺.

Step 4

Reaction of the product of Step 3 with HCl by essentially the procedureof Example 3, Step 2 gave the product.

Step 5

Reaction of the product of Step 4 with methanesulfonyl chloride byessentially the procedure of Example 3, Step 3 gave the product. ¹H NMR(CDCl₃, 400 MHz) δ 7.64 (2H, m), 7.48 (1H, m), 7.17 (1H, m), 4.44 (1H,m), 3.95 (2H, m), 3.06 (3H, s), 2.81 (3H, s), 2.80 (2H, m), 1.90 (4H,m). MS m/e 414 (M+H)⁺.

EXAMPLE 14

Reaction of the product of Example 13, Step 4 (13-4) with acetylchloride by essentially the procedure of Example 4 gave the product. ¹HNMR (CDCl₃, 400 MHz) δ 11.00 (1H, b), 7.65 (2H, m), 7.50 (1H, m), 7.17(1H, m), 4.80 (1H, m), 4.55 (1H, m), 3.94 (1H, m), 3.20 (1H, m), 3.09(3H, s), 2.63 (1H, m), 2.13 (3H, s), 1.70 (4H, m). MS m/e 378 (M+H)⁺.

EXAMPLE 15

To an ice-cold solution of the product of Example 13, Step 4 (13-4) (25mg, 0.074 mmol) in DMF (5 ml) was added methyl isocyanate (1 drop). Thereaction mixture was allowed to warm to R.T., stirred for 3 days, thendiluted with CH₂Cl₂ and washed with water, 1N NaOH, and sat'd NaCl. Theorganic layer was dried (Na₂SO₄), filtered and evaporated. The residuewas subjected to PTLC (10:90 MeOH/CH₂Cl₂) to give the product (9 mg,31%). ¹H NMR (CDCl₃, 400 MHz) δ 10.80 (1H, b), 7.64 (2H, m), 7.45 (1H,m), 7.19 (1H, m), 4.48 (1H, m), 4.10 (2H, m), 3.10 (3H, s), 2.90 (3H,s), 2.85 (2H, m), 1.78 (4H, m). MS m/e 393 (M+H)⁺.

EXAMPLE 16

Reaction of 12-4 with methyl isocyanate by essentially the sameprocedure gave the product. ¹H NMR (CDCl₃, 400 MHz) δ 7.48 (1H, s), 7.28(3H, m), 7.03 (1H, d, J=4 Hz), 6.87 (1H, m), 6.50 (1H, d, J=4 Hz), 4.56(1H, m), 4.44 (1H, m), 4.03 (2H, m), 2.87 (2H, m), 2.86 (3H, s), 2.80(3H, s), 2.04-1.54 (4H, m). MS m/e 392 (M+H)⁺.

EXAMPLE 17

Step 1

To a solution of the product of Example 1, Step 2 (1-2) (250 mg, 1.21mmol) in toluene (8 ml) was added iPr₂NEt (1.1 ml, 6.0 mmol) andtriphosgene (145 mg, 0.49 mmol). The reaction mixture was heated to 110°C. for 4 hr, cooled, and Preparation 13 (250 mg, 1.47 mmol) was added.The reaction mixture was stirred for 16 hr, then partitioned betweenCH₂Cl₂ (100 ml) and 1N NaOH (25 ml). The organic layer was washed withsat. NH₄Cl (25 ml) and sat'd NaCl (25 ml), dried (MgSO₄), filtered andconcentrated. The residue was dissolved in THF (20 ml) to which 5N HCl(5 ml) was added. After 3.5 hr, the reaction mixture was cooled in anice bath, basified to pH 12 and partitioned between CH₂Cl₂ (100 ml) andwater (25 ml). The organic layer was dried (MgSO₄), filtered andconcentrated. Subjection of the residue to PTLC (3:2 EtOAc/hexane) gavethe product (130 mg, 30%). MS m/e 360 (M+H)⁺.

Step 2

To a solution of the product of Step 1 (60 mg, 0.17 mmol) in EtOH (2.5ml) was added NaOAc (0.27 g, 3.3 mmol) and hydroxylamine hydrochloride(0.23 g, 3.34 mmol). The reaction mixture was stirred for 16 hr, thenpartitioned between CH₂Cl₂ (75 ml) and water (50 ml). The organic layerwas dried (MgSO₄), filtered and concentrated. The residue was subjectedto PTLC (3:97 MeOH/CH₂Cl₂) to give the product (52 mg, 83%). ¹H NMR(CD₃OD, 400 MHz) δ 8.69 (1H, m), 8.00 (1H, m), 7.80 (1H, m), 7.55 (4H,m), 6.94 (1H, m), 4.40 (1H, m), 3.45 (1H, m), 2.91 (3H, s), 2.50 (1H,m), 2.30 (1H, m), 1.90 (3H, m), 1.70 (2H, m). MS m/e 375 (M+H)⁺.

EXAMPLE 18

Reaction of the amine 1-2, N,N′-disuccinimidyl carbonate, andPreparation 12 by essentially the procedure of Example 2, Step 3 gavethe product. ¹H NMR (DMSO, 400 MHz) δ 8.76 (1H, s), 8.66 (1H, s), 7.96(2H, m), 7.73 (2H, d), 7.21 (1H, m), 6.77 (2H, s), 4.09 (1H, m), 3.55(2H, m), 2.85 (3H, s), 2.61 (2H, m), 1.76 (2H, m), 1.64 (2H, m). MS m/e426 (M+H)⁺.

EXAMPLE 19

Step 1

To a suspension of 2-amino-5-nitropyrimidine (2.70 g, 19.3 mmol) andLiCl (20 g) in 4M HCl (95 ml) at −10° C. was added NaNO₂ (2.70 g, 39.1mmol) in portions. The suspension was stirred at ice-bath temperaturefor 1 hr, then allowed to warm to R.T. and stirred for 1.5 hr. Thereaction mixture was cooled in an ice-bath, CH₂Cl₂ (50 ml) was added andaqueous layer was brought to pH 9 by addition of sat'd Na₂CO₃. The wholewas filtered and the filtrate was extracted with CH₂Cl₂. The organiclayer was dried (MgSO₄), filtered and evaporated to give a solid (1.05g, 34%). ¹H NMR (CDCl₃, 400 MHz) δ 9.39 (s).Step 2

To an N₂-purged mixture of the product of Step 1 (230 mg, 1.44 mmol),3,5-difluorophenylboronic acid (655 mg, 2.08 mmol), CsCO₃ (502 mg, 1.54mmol), H₂O (0.05 ml), and toluene (3 ml) was added Pd(dppf)Cl₂.CH₂Cl₂(82 mg, 0.10 mmol). The reaction mixture was heated at 110° C. for 1.5hr, then allowed to cool. EtOAc (20 ml) and H₂O (20 ml) was added, andthe organic layer was dried (MgSO₄), filtered and evaporated. Flashchromatography of the residue (1:99 EtOAc/hexanes) gave the product (110mg, 32%). ¹H NMR (CDCl₃, 400 MHz) δ 9.54 (2H, s), 8.08 (2H, m), 7.03(1H, m).Step 3

To an ice-cold suspension of the product of Step 2 (110 mg, 0.46 mmol)and NiCl₂.6H₂O (240 mg, 1.01 mmol) in MeOH (4 ml) was added NaBH₄ (57mg, 1.51 mmol). The reaction mixture was stirred for 10 min., then H₂O(2 ml) was added and the mixture was concentrated. To the residue wereadded H₂O (20 ml) and CH₂Cl₂ (30 ml), and the whole was filtered. Theorganic layer of the filtrate was dried (Na₂SO₄), filtered andevaporated to give a solid (72 mg, 75%). MS (m/e) 208 (M+H)⁺.

Step 4

Reaction of the product of Step 3 (70 mg, 0.34 mmol) with Preparation 11(98 mg, 0.51 mmol) by the procedure of Example 2, Step 3 gave theproduct (90 mg, 62%). ¹H NMR (CDCl₃, 400 MHz) δ 8.91 (2H, s), 7.90 (2H,m), 6.86 (1H, m), 6.64 (1H, s), 4.42 (1H, m), 3.91 (2H, m), 2.95 (3H,s), 2.80 (5H, m), 1.81 (4H, m). MS (m/e) 426 (M+H)⁺.

Use of the appropriate procedures afforded the following compounds:STRUCTURE ¹H NMR MS (M + H)⁺

19A (CDCl₃) δ 8.92(s, 2H), 7.90(m, 2H), 6.87(m, 1H), 6.52(s, 1H),4.43(m, 1H), 4.22(m, 2H), 2.95(s, 3H), 2.82(m, 2H), 1.78-1.52(m, 4H),1.47(s, 9H). 448

19B (CDCl₃) δ 8.92(s, 2H), 7.90(m, 2H), 6.86(m, 1H), 6.52(s, 1H),4.46(m, 1H), 3.93(m, 2H), 2.95(m, 7H), 1.81(m, 4H), 1.36(t, 3H). 440

19C (CD₃OD) δ 8.99(s, 2H), 7.91(m, 2H), 7.04(m, 1H), 4.28(m, 1H),3.86(m, 2H), 2.95(m, 7H), 1.84(m, 6H), 1.07(t, 3H). 454

19D (CDCl₃) δ 8.92(s, 2H), 7.90(m, 2H), 6.86(m, 1H), 6.49(s, 1H),4.48(m, 1H), 3.96(m, 2H), 3.21(m, 1H), 2.95(m, 5H), 1.77(m, 4H), 1.36(m,6H). 454

19E (CDCl₃) δ 8.92(s, 2H), 7.91(m, 2H), 6.87(m, 1H), 6.63(s, 1H),4.44(m, 1H), 3.90(m, 2H), 2.95(m, 5H), 2.28(m, 1H), 1.82(m, 4H), 1.15(m,2H), 1.00 (m, 2H). 452

19F (CDCl₃) δ 8.92(s, 2H), 7.90(m, 2H), 6.87(m, 1H), 6.77(s, 1H),4.78(m, 1H), 4.52(m, 1H), 3.92(m, 1H), 3.18(m, 1H), 2.94(s, 3H), 2.61(m,1H), 2.11(s, 3H), 1.82-1.57(m, 4H). 390

19G (CDCl₃) δ 8.92(s, 2H), 7.90(m, 2H), 6.87(m, 1H), 6.74(s, 1H),4.78(m, 1H), 4.52(m, 1H), 3.95(m, 1H), 3.12(m, 1H), 2.93(s, 3H), 2.61(m,1H), 2.38(m, 2H), 1.82-1.55(m, 4H), 1.35(t, 3H). 404

19H (CDCl₃) δ 8.92(s, 2H), 7.90(m, 2H), 6.87(m, 1H), 6.64(s, 1H),4.80(m, 1H), 4.55(m, 1H), 4.06(m, 1H), 3.16(m, 1H), 2.93(s, 3H), 2.62(m,1H), 1.79-1.57(m, 5H), 0.98(m, 2H), 0.78(m, 2H). 416

19I (CDCl₃) δ 8.92(s, 2H), 7.90(m, 2H), 6.87(m, 1H), 6.64(s, 1H),4.81(m, 1H), 4.53(m, 1H), 4.06(m, 1H), 3.16(m, 1H), 2.94(s, 3H), 2.80(m,1H), 2.59(s, 1H), 1.79(m, 2H), 1.57(m, 2H), 1.14 (m, 6H). 418

19J (CD₃OD) δ 9.04(s, 2H), 7.90(m, 2H), 7.08(m, 1H), 4.69(m, 1H),4.40(m, 1H), 4.11(m, 1H), 3.22(m, 1H), 2.95(s, 3H), 2.72(m, 1H), 2.42(t,2H), 1.78-1.62(m, 6H), 1.00(t, 3H). 418

19K (CDCl₃) δ 8.92(s, 2H), 8.69(s, 2H), 7.91(d, J=6.8 Hz, 2H), 7.79(s,J=7.6 Hz, 1H), 7.40(m, 1H), 6.87(m, 1H), 6.56(s, 1H), 4.87(m, 1H),4.60(m, 1H), 3.87(m, 1H), 3.24(m, 1H), 2.98(m, 4H), 1.95-1.48(m,4H). 453

19L (CDCl₃) δ 8.92(s, 2H), 8.59(m, 1H), 7.90(m, 2H), 7.80(m, 1H),7.62(d, J=7.2 Hz, 1H), 7.36(m, 1H), 6.87(m, 1H), 6.70(s, 1H), 4.89(m,1H), 4.60(m, 1H), 4.09(m, 1H), 3.16(m, 1H), 2.96(s, 3H), 2.88(m, 1H),1.84-1.72(m, 4H). 453

19M (CDCl₃) δ 8.94(s, 2H), 8.90(s, 1H), 8.07(s, 7.90(m, 2H), 6.87(m,1H), 6.59(s, 1H), 4.80-4.20(m, 3H), 3.30-2.80(m, 5H), 1.86-1.69(m, 4H).459

EXAMPLE 20

Step 1

To an ice-cold suspension of (methoxymethyl)triphenylphosphoniumchloride (30.4 g, 89 mmol) in Et₂O (250 ml) was added 1.8 Mphenyllithium (49.3 ml, 89 mmol) dropwise under N₂. After the additionwas complete, the reaction mixture was stirred at 0° C. for 0.25 hr,then at R.T. for 0.5 hr. The reaction mixture was cooled to −10° C. and3-fluorobenzaldehyde (10 g, 81 mmol) was added dropwise. The reactionmixture was stirred at R.T. overnight, then sat'd NH₄Cl was added. Theaqueous layer was extracted with Et₂O (2×), and the combined organiclayers were dried (Na₂SO₄), filtered, and concentrated. Flashchromatography (hexane) of the residue afforded the product (8.67 g,70%) as a mixture of isomers. ¹H NMR (CDCl₃, 400 MHz, major isomer) δ7.36 (1H, m), 7.32 (1H, m), 7.07 (1H, d, J=17 Hz), 6.96 (1H, m), 6.93(1H, m), 5.77 (1H, d, J=17 Hz), 3.70 (3H, s).Step 2

To an ice-cold solution of the product of Step 1 (8.67, 57 mmol) in MeOH(200 ml) was added N-bromosuccinimide (10.14 g, 57 mmol), and thereaction mixture was stirred at R.T. for 16 hr. The reaction mixture wasconcentrated, taken up in EtOAc, washed with 1M HCl and sat'd NaCl, thendried (Na₂SO₄), filtered and concentrated. Subjection of the residue toflash chromatography (90:10 hexane/EtOAc) gave the product (11.8 g,80%). ¹H NMR (CDCl₃, 400 MHz) δ 7.32 (1H, m), 7.16 (2H, m), 6.99 (1H,m), 4.90 (1H, d, J=9 Hz), 4.70 (1H, d, J=9 Hz), 3.49 (3H, s), 3.31 (3H,s).Step 3

A mixture of the product of Step 2 (11.5 g, 43.7 mmol), thiourea (6.0 g,79 mmol) and 48% HBr (0.1 ml) was stirred at 100° C. for 3 hr. Thereaction mixture was allowed to cool to R.T., acidified with 6N HCl, andwashed with CH₂Cl₂. The aqueous layer was brought to pH 9 by addition ofaqueous NH₄OH and the resultant precipitate was collected. Subjection ofthe dried precipitate to flash chromatography (2:98 then 5:95MeOH/CH₂Cl₂) gave the product (1.61 g, 19%). ¹H NMR (CDCl₃, 400 MHz) δ7.30 (2H, m), 7.18 (1H, m), 7.11 (1H, m), 6.93 (1H, m), 5.07 (2H, b).Step 4

To a stirred suspension of NaH (103 mg, 2.6 mmol, 60% dispersion) in THF(30 ml) under N₂ was added the product of Step 3 (500 mg, 2.6 mmol).After 1 hr, the reaction mixture was cooled in an ice bath, and phenylchloroformate (0.32 ml, 2.6 mmol) in THF (20 ml) was added dropwise. Thereaction mixture was stirred for 16 hr, during which time it attainedR.T. The reaction mixture was diluted with EtOAc, washed with sat'dNH₄Cl solution, dried (Na₂SO₄), filtered and concentrated. Subjection ofthe residue to flash chromatography (CH₂Cl₂) afforded the product (0.39g, 48%). ¹H NMR (CDCl₃, 400 MHz) δ 7.65 (1H, s), 7.48 (2H, m), 7.38-7.20(6H, m), 7.00 (1H, m), 2.9 (1H, b). MS (m/e) 315 (M+H)⁺.Step 5

A mixture of the product of Step 4 (390 mg, 1.24 mmol), Preparation 1(266 mg, 1.24 mmol) and Et₃N (0.5 ml, 3.6 mmol) in THF (25 ml) wasrefluxed for 3 hr. The reaction mixture was allowed to cool, dilutedwith EtOAc, washed with sat'd NH₄Cl solution, dried (Na₂SO₄), filteredand concentrated. Subjection of the residue to flash chromatography(2:98 MeOH/CH₂Cl₂) afforded the product (537 mg, 100%). ¹H NMR (CDCl₃,400 MHz) δ 9.54 (1H, b), 7.51 (1H, s), 7.29 (3H, m), 6.96 (1H, m), 4.39(1H, m), 4.21 (2H, b), 2.88 (3H, s), 2.78 (2H, m), 1.63 (4H, m), 1.45(9H, s). MS (m/e) 435 (M+H)⁺.Step 6

Reaction of the product of Step 5 with HCl by essentially the procedureof Example 6, Step 4 gave the product. ¹H NMR (CD₃OD, 400 MHz) δ 8.00(1H, s), 7.58-7.41 (3H, m), 7.19 (1H, m), 4.42 (1H, m), 3.54 (2H, m),3.20 (2H, m), 3.07 (3H, s), 2.15 (2H, m), 2.01 (2H, m). MS (m/e) 335(M+H)⁺.

Step 7

Reaction of the product of Step 6 (20 mg, 0.05 mmol) with methylisocyanate (1 drop) by essentially the procedure of Example 15 followedby PTLC (10:90 MeOH/CH₂Cl₂) gave the product (7 mg, 36%). MS m/e 392(M+H)⁺.

EXAMPLE 21

Reaction of 20-6 with acetyl chloride essentially the procedure ofExample 4 gave the product. MS m/e 377 (M+H)⁺.

EXAMPLE 22

Reaction of 20-6 with methanesulfonyl chloride by the procedure ofExample 3, Step 3 gave the product. ¹H NMR (CDCl₃, 400 MHz) δ 7.52 (1H,s), 7.34 (1H, m), 7.22 (1H, m), 7.21 (1H, m), 6.97 (1H, m), 4.40 (1H,m), 3.92 (2H, m), 2.91 (3H, s), 2.79 (3H, s), 2.75 (2H, m), 1.83 (4H,m). MS m/e 413 (M+H)⁺.

EXAMPLE 23

Step 1

To a solution of 2-bromo-5-nitrothiazole (0.784 g, 3.75 mmol) and 0.5 M3,5-difluorophenylzinc bromide in THF (5.0 ml, 12.5 mmol) was addedPd(PPh₃)₄ (0.173 g, 0.15 mmol) under argon. The reaction mixture wasstirred at R.T. for 30 min. then poured into water (25 ml). The wholewas extracted with CH₂Cl₂ (3×50 ml) dried (Na₂SO₄), filtered, andevaporated. The residue was subjected to PTLC (1:10 EtOAc/hexane) togive the product (0.49 g, 81%). ¹H NMR (CDCl₃) δ 8.59 (s, 1H), 7.52 (m,2H), 7.01 (m, 1H). MS m/e 243 (M+H)⁺.Step 2

To a solution of the product of Step 1 (0.300 g, 1.24 mmol) in MeOH (20ml) was added nickel chloride hexahydrate (0.589 g, 2.48 mmol) andsodium borohydride (0.187 g, 4.95 mmol) at 0° C. The reaction mixturewas stirred at R.T. for 10 min. and quenched with water (10 ml). Themixture was filtered via celite. The celite was washed with CH₂Cl₂ (100ml). The filtrate was extracted with CH₂Cl₂ (3×50 ml), and the combinedorganic layers were dried (Na₂SO₄), filtered, and evaporated. Theresidue was subjected to PTLC (1:2 EtOAc/hexane) to give the product(0.060 g, 23%). ¹H NMR (CDCl₃) δ 7.30 (m, 2H), 7.1 (s, 1H), 6.77 (m,1H), 3.90 (bs, 2H). MS m/e 213 (M+H)⁺.Step 3

To a solution of the product of Step 2 (0.080 g, 0.377 mmol) inanhydrous pyridine (3.0 ml) was added phenyl chloroformate (0.071 ml,0.566 mmol) slowly. The reaction mixture was stirred at R.T. overnightand evaporated. To a solution of the residue in chloroform (5 ml) andwas added Preparation 1 (0.122 g, 0.567 mmol) and Et₃N (0.16 ml, 1.13mmol). The reaction mixture was refluxed for 21 hr, allowed to cool andpoured into water (25 ml). The whole was extracted with CH₂Cl₂ (3×50ml), dried (Na₂SO₄), filtered and evaporated (1:20 MeOH/CH₂Cl₂) to givethe product (0.087 g, 51%) as a solid. ¹H NMR (CDCl₃) δ 7.78 (s, 1H),7.43 (s, 1H), 7.36 (m, 2H), 6.78 (m, 1H), 4.4 (bs, 1H), 4.2 (bs, 1H),3.82 (bs, 1H), 2.89 (s, 3H), 2.78 (m, b, 2H), 1.8-1.5 (m, 4H), 1.45 (s,9H). MS m/e 453 (M+H)⁺.

Step 4

Subjection of the product of Step 3 to the procedures of Example 3,Steps 2 and 3 gave the product. ¹H NMR (CDCl₃) δ 8.04 (s, 1H), 7.54 (s,1H), 7.38 (m, 2H), 6.78 (m, 1H), 4.78 (m, 1H), 4.51 (m, 1H), 3.95 (m,1H), 3.20 (m, 1H), 2.92 (m, 3H), 2.61 (m, 1H), 2.11 (s, 3H), 1.75 (m,2H), 1.59 (m, 2H). MS m/e 395 (M+H)⁺.

Use of the appropriate reagents and procedures afforded the followingcompounds: STRUCTURE ¹H NMR MS (M + H)⁺

23A (CDCl₃) δ 7.52(s, 1H), 7.40(m, 3H), 6.80(m, 1H), 4.22(m, 1H),3.93(m, 2H), 2.94(s, 3H), 2.77 (m, 5H), 1.82(m, 4H). 431

23B (CDCl₃) δ 7.51(s, 1H), 7.41(m, 3H), 6.80(m, 1H), 4.80(m, 1H),4.50(m, 1H), 3.95(m, 1H), 3.15 (m, 1H), 2.91(s, 3H), 2.60(m, 1H),2.32(m, 2H), 1.80-1.50(m, 6H), 0.98(t, 3H). 423

23C (CDCl₃) δ 7.52(s, 1H), 7.46(s, 1H), 7.40(m, 2H), 6.79(m, 1H),4.80(m, 1H), 4.50(m, 1H), 4.15 (m, 1H), 3.15(m, 1H), 2.89(s, 3H),2.70(m, 1H), 2.60(m, 1H), 1.9-1.5(m, 12H). 449

23D (CDCl₃) δ 7.62(s, 1H), 7.47(s, 1H), 7.40(m, 2H), 6.80(m, 1H),4.78(m, 1H), 4.50(m, 1H), 4.32 (m, 1H), 3.20(m, 1H), 2.91(s, 3H),2.62(m, 1H), 1.80-1.60(m, 5H), 0.99(m, 2H), 0.80(m, 2H). 421

23E (CDCl₃) δ 7.73(s, 1H), 7.46(s, 1H), 7.38(m, 2H), 6.80(m, 1H),4.80(m, 1H), 4.50(m, 1H), 4.03 (m, 1H), 3.14(m, 1H), 2.91(s, 3H),2.82(m, 1H), 2.59(m, 1H), 1.95-1.62(m, 2H), 1.57(m, 2H), 1.16(m, 6H).423

23F (CDCl₃) δ 7.49(s, 1H), 7.45(s, 1H), 7.40(m, 2H), 6.79(m, 1H),4.80(m, 1H), 4.50(m, 1H), 3.95 (m, 1H), 3.18(m, 1H), 2.91(s, 3H),2.60(m, 1H), 2.37(q, 2H), 1.80-1.50(m, 4H), 1.16(t, 3H). 409

EXAMPLE 24

Step 1

A flask charged with 3,5-difluorophenylboronic acid (4.40 g, 27.9 mmol),2-amino-5-bromopyrimidine (4.00 g, 23 mmol), toluene (40 ml), water (7ml) and cesium carbonate (8.20 g, 25.2 mmol) was purged with N₂.PdCl₂(dppf)₂.CH₂Cl₂ (0.94 g, 1.15 mmol) was added and the reactionmixture was refluxed for 2.5 hr. The reaction mixture was allowed tocool then poured into water (100 ml). The whole was extracted with EtOAc(3×150 ml), dried (Na₂SO₄), filtered and concentrated. Subjection of theresidue to flash chromatography (gradient 1:5 to 1:1 acetone/hexane)gave the product (2.30 g, 48%). ¹H NMR (CDCl₃) δ 8.29 (s, 2H), 6.84 (m,2H), 6.62 (m, 1H), 4.18 (s, 2H). MS m/e 208 (M+H)⁺.Step 2

To a solution of the product of Step 1 (0.500 g, 2.42 mmol) in anhydrouspyridine (6 ml) was added phenyl chloroformate (0.33 ml, 2.62 mmol)dropwise. The reaction mixture was stirred for 16 hr, then evaporated.The residue was subjected to PTLC (1:30 CH₃OH/CH₂Cl₂) to give theproduct (0.30 g, 38%). ¹HNMR (CDCl₃) δ 8.84 (m, 3H), 7.42 (m, 2H), 7.26(m, 3H), 7.06 (m, 2H), 6.89 (m, 1H). MS m/e 328 (M+H)⁺.Step 3

To a solution of the product of Step 2 (0.145 g, 0.44 mmol) inchloroform (5 ml) was added Preparation 1 (0.095 g, 0.44 mmol) and Et₃N(0.19 ml, 1.33 mmol). The reaction mixture was refluxed for 3 hr,allowed to cool and poured into water (15 ml). The whole was extractedwith EtOAc (3×), and the combined organic layers were dried (Na₂SO₄),filtered and evaporated. The residue was subjected to PTLC (1:30CH₃OH/CH₂Cl₂) to give the product (0.205 g, 100%). ¹H NMR (CDCl₃) δ 8.71(s, 2H), 7.70 (s, b, 1H), 7.01 (m, 2H), 6.83 (m, 1H), 4.36 (m, 1H), 4.21(m, 2H), 2.92 (s, 3H), 2.78 (m, 2H), 1.74 (m, 2H), 1.63 (m, 2H), 1.45(s, 9H). MS m/e 448 (M+H)⁺.

Step 4

Subjection of the product of Step 3 to the procedures of Example 10,Steps 3 and 4 gave the product. ¹H NMR (CDCl₃) δ 8.71 (s, 2H), 7.62 (s,b, 1H), 7.02 (m, 2H), 6.84 (m, 1H), 4.78 (m, 1H), 4.43 (m, 1H), 3.90 (m,1H), 3.18 (m, 1H), 2.92 (s, 3H), 2.60 (m, 1H), 2.09 (s, 3H), 1.82 (m,2H), 1.60 (m, 2H). MS m/e 390 (M+H)⁺.

Use of the appropriate reagents and procedures afforded the followingcompounds. STRUCTURE ¹H NMR MS (M + H)⁺

24A (CDCl₃) δ 8.74(s, 2H), 7.42(s, b, 1H), 7.04(m, 2H), 6.83(m, 1H),4.43(m, 1H), 3.95(m, 2H), 2.97(s, 3H), 2.80(m, 5H), 1.88 (m, 4H). 426

24B (CDCl₃) δ 8.73(s, b, 2H), 7.59 (s, b, 1H), 7.03(m, 2H), 6.83(m,1H),4.79(m, 1H), 4.47(m, 1H), 3.94(m, 1H), 3.09(m, 1H), 2.92 (s, 3H),2.59(m, 1H), 2.35(m, 2H), 1.82(m, 2H), 1.61(m, 2H), 1.15(m, 3H). 404

EXAMPLE 25

Step 1

A mixture of 3,6-dichloropyridazine (7.5 g) and NH₃ (9 g) in EtOH (100ml) was heated at 130° C. in stainless steel bomb for 16 hr. After thereaction mixture had cooled to R.T., it was concentrated, and theresidue was subjected to Soxhlet extraction (EtOAc). The residueobtained from the EtOAc extract was recrystallized from EtOAc to givethe product (3.81 g).Step 2

A suspension of the product of Step 1 (200 mg, 1.54 mmol),3-fluorophenylboronic acid (260 mg, 1.86 mmol), and 2M K₂CO₃ (1.6 ml,3.2 mmol) in EtOH (3 ml) and toluene (10 ml) was purged with N₂.Pd(PPh₃)₄ (90 mg, 0.08 mmol) was added, and the mixture was heated at110° C. for 24 hr. The cooled reaction mixture was concentrated andpartitioned between water and EtOAc. The organic layer was washed withwater, dried (Na₂SO₄), filtered and evaporated. Subjection of theresidue to PTLC (7:93 MeOH/CH₂Cl₂) gave the product (168 mg, 58%).Step 3

Reaction of the product of Step 2 by essentially the procedure ofExample 20, Step 4 gave the product. ¹H NMR (CDCl₃, 400 MHz) δ 8.75 (1H,b), 8.43 (1H, m), 7.95 (1H, m), 7.82-7.78 (2H, m), 7.52-7.18 (7H, m). MSm/e 310 (M+H)⁺.Step 4

Reaction of the product of Step 3 with Preparation 1 by essentially theprocedure of Example 20, Step 5 gave the product. ¹H NMR (CDCl₃, 400MHz) δ 8.6 (1H, b), 8.36 (1H, m), 7.80 (1H, m), 7.73 (2H, m), 7.44 (1H,m), 7.12 (1H, m), 4.41 (1H, m), 4.21 (2H, m), 2.99 (3H, s), 2.80 (2H,m), 1.79-1.60 (4H, m), 1.43 (9H, s). MS m/e 430 (M+H)⁺.

Step 5

Subjection of the product of Step 4 by the procedure of Example 20,Steps 6 and 7 gave the product. ¹H NMR (CDCl₃, 400 MHz) δ 8.40 (1H, m),8.20 (1H, b), 7.82 (1H, m), 7.50 (2H, m), 7.42 (1H, m), 7.15 (1H, m),4.54 (1H, m), 4.44 (1H, m), 4.09 (2H, m), 2.98 (3H, s), 2.90 (2H, m),2.79 (3H, s), 1.75-1.64 (4H, m). MS m/e 387 (M+H)⁺.

Use of the appropriate procedures afforded the following compounds:

EXAMPLE 26

¹H NMR (CDCl₃, 400 MHz) 68.6 (1H, b), 8.34 (1H, m), 7.80 (1H, m), 7.73(2H, m), 7.44 (1H, m), 7.13 (1H, m), 4.76 (1H, m), 4.50 (1H, m), 3.89(1H, m), 3.15 (1H, m), 2.99 (3H, s), 2.25 (1H, m), 2.09 (3H, s), 1.79(2H, m), 1.63 (2H, m). MS m/e 372 (M+H)⁺.

EXAMPLE 27

¹H NMR (CDCl₃, 400 MHz) δ 8.47 (1H, m), 7.86 (1H, m), 7.77 (2H, m), 7.47(1H, m), 7.17 (1H, m), 4.47 (1H, m), 3.97 (2H, m), 3.02 (3H, s), 2.83(2H, m), 2.82 (3H, s), 1.93-1.50 (4H, m). MS m/e 408 (M+H)⁺.

1. A compound of Formula I:

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein =A-B= is ═C(R⁴)—C(R⁵)═ and —X═Y— is —C(R⁶)═N—, —N═C(R⁷)—, —N═N— or —S—, or =A-B= is ═N—C(R⁵)═ and —X═Y— is —N═C(R⁷)—, —C(R⁶)═N—, —S— or —O—, or =A-B= is ═C(R⁴)—N═ and —X═Y— is —C(R⁶)═N—, —S— or —O—, or =A-B= is ═N—N═ and —X═Y— is —S— or —O—, or =A-B= is ═C(R⁴)— and —X═Y— is —S—N═, —N(R¹⁰)—N═, or =A-B= is —C(R⁴)═ and —X═Y— is ═N—S—, or ═N—N(R¹⁰)—; Z is

R¹ is H or —(C₁-C₆)alkyl; R² is H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl or —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl; R³ is

Q is —OR¹³, or —NR¹³R¹⁴; j is 1 or 2; k is 0, 1 or 2; l is 0, 1 or 2; m is 0, 1 or 2; n is 0 to 6; p is 1, 2 or 3; q is 1 or 2; R⁴, R⁵, R⁶ and R⁷ may be the same or different, and are independently selected from H, —OH, halogen, haloalkyl, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —CN, NR¹⁰R¹¹, NR¹³R¹⁴, —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl(C₃-C₇)cycolalkyl, —S(C₁-C₆)alkyl, —S(C₃-C₇)cycloalkyl and —S(C₁-C₆)alkyl(C₃-C₇)cycloalkyl; R⁸ may be the same or different, and is independently selected from H, halogen, —OH, haloalkyl, haloalkoxy, —CN, —NO₂, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, NR¹⁰R¹¹, NR¹³R¹⁴, —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl(C₃-C₇)cycloalkyl and —CONR¹³R¹⁴; R⁹ is —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)haloalkyl, —SO₂[hydroxy(C₂-C₆)alkyl], —SO₂[amino(C₂-C₆)alkyl], —SO₂[alkoxy(C₂-C₆)alkyl], —SO₂[alkylamino(C₂-C₆)alkyl], —SO₂[dialkylamino(C₂-C₆)alkyl], —SO₂(aryl), —SO₂(heteroaryl), —SO₂[aryl(C₁-C₆) alkyl], —SO₂NR¹³R¹⁴, —CO(C₁-C₆)alkyl, —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, CO(C₁-C₆)haloalkyl, —C(O)aryl, —C(O)heteroaryl, —CONR¹³R¹⁴, —C(S)NR¹³R¹⁴, aryl, heteroaryl, —(CH₂)CONR¹³R¹⁴, —C(═NCN)alkylthio, —C(═NCN)NR¹³R¹⁴, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alky (C₃-C₇)cycloalkyl, —(C₁-C₆)alkylaryl, —(C₁-C₆)alkylheteroaryl or —COOR¹²; R¹⁰ is H or alkyl; R¹¹ is H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, aryl, heteroaryl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)haloalkyl, —SO₂(aryl), —SO₂(heteroaryl), —CO(C₁-C₆)alkyl, —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —C(O)aryl, —C(O)heteroaryl, —CONR¹³R¹⁴ or —COOR¹²; R¹² is —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylaryl, —(C₁-C₆)alkylheteroaryl, aryl or heteroaryl; R¹³ and R¹⁴ may be the same or different and are independently H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylaryl, aryl or heteroaryl; and, R¹⁵ may be the same or different, and is H, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, aryl, heteroaryl, —CN, —CONR¹³R¹⁴, —COOR¹³, —OH, —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, —O(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —NR¹⁰R¹¹, —NR¹³R¹⁴, or a —(C₁-C₆)alkyl group substituted by an aryl, heteroaryl, hydroxy, alkoxy, —NR¹⁰R¹¹, —NR¹³R¹⁴, —CONR¹³R¹⁴, or —COOR¹³ group.
 2. A compound as defined in claim 1 wherein

R¹⁵ is H and R³ is

the sum of j and k is 2 or 3; and the sum of l and m is 2 or
 3. 3. A compound as defined in claim 1 wherein R¹ is hydrogen, R² is hydrogen or (C₁-C₆)alkyl, R⁴, R⁵, R⁶ and R⁷ are hydrogen or halogen, R⁸ may be the same or different, and is independently selected from H, halogen, —O(C₁-C₆)alkyl, —OH, haloalkyl and haloalkoxy, R⁹ is —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl, —SO₂(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —SO₂aryl, —SO₂heteroaryl, —SO₂NR¹³R¹⁴, —CO(C₁-C₆)alkyl, —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —C(O)aryl, —C(O)heteroaryl, aryl, heteroaryl, R¹⁰ is H or —(C₁-C₆)alkyl, R¹¹ is —SO₂(C₁-C₆)alkyl, Q is —OR¹³ or —NR¹³R¹⁴; R¹³ and R¹⁴ may be the same or different, and are independently H or —(C₁-C₆)alkyl; the sum of j and k is 2 or 3; the sum of l and m is 2 or 3; and n is 0 to
 6. 4. A compound as defined in claim 1 wherein R¹⁵ is H and R³ is

R⁹ is —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₇)cycloalkyl, —SO₂aryl, —SO₂heteroaryl, —CO(C₁-C₆)alkyl, —CO(C₃-C₇)cycloalkyl, —CO(C₁-C₆)alkyl(C₃-C₇)cycloalkyl, —C(O)aryl, —C(O)heteroaryl, aryl, or heteroaryl, and the sum of j and k is 2 or
 3. 5. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 1

3 —SO₂CH₃ 4

1G

1H

1I

3E

3F

3G

3H

4B

4C

4D

4E

4F

4G

4H

4I

4J

4K

4L

4M

4N

4O

4P


6. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 3I —SO₂CH₃ 3J

3K

3L

4Z

4AA

4BB

4CC

4DD

4EE

4FF


7. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 3N —SO₂CH₃ 3O


8. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 5

5A —SO₂CH₃ 5B

5C

5D

5E

5F

5G

5H

5I

5J

5K


9. The compound as defined in claim 3 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 5M —SO₂CH₃ 5N

5O

5P

5Q


10. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 6

6B —SO₂CH₃ 6C

6D


11. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein Z and R⁹ are as shown in the table below: Example Z R⁹ 7

7B

—SO₂CH₃ 7C

7D

7E

7F

—SO₂CH₃ 7G


12. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 10

10A

10B

10C

10D

10E

10F

10G

10H

10I

10J

10K

10L

10M

10N

10O

10P

10Q

10W —SO₂CH₃


13. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 10S —SO₂CH₃ 10T

10U

10V


14. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein Z and R⁹ are as shown in the table below: Example Z R⁹ 10X

—SO₂CH₃ 10Y

10Z

10AA

10BB

10CC

10DD

10EE

10FF

10GG

10HH

10II

10JJ

10KK

10LL

10MM

10NN

10OO

10PP

10QQ

10RR

11

—SO₂CH₃ 11A

—SO₂CH₃ 11B

—SO₂CH₃ 11C

—SO₂CH₃ 11D

—SO₂CH₃ 11E

—SO₂CH₃


15. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 19 —SO₂CH₃ 19A

19B

19C

19D

19E

19F

19G

19H

19I

19J

19K

19L

19M


16. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 24

24A —SO₂CH₃ 24B


17. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein R⁹ is as shown in the table below: Example R⁹ 25

26

27 —SO₂CH₃


18. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein Z and R⁹ are as shown in the table below: Example Z R⁹ 12

—SO₂CH₃ 12A

—SO₂CH₃ 12B

12C

12D

12E

12F

12G

12H

12I

12J

12K

12L

12M

12N

16


19. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein Z and R⁹ are as shown in the table below: Example Z R⁹ 20

21

22

—SO₂CH₃


20. The compound as defined in claim 1 of the formula

or a pharmaceutically acceptable salt and/or hydrate of said compound, wherein Z and R⁹ are as shown in the table below: Example Z R⁹ 23

23A

—SO₂CH₃ 23B

23C

23D

23E

23F


21. A pharmaceutical composition which comprises an effective amount of a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.
 22. A method of treating an eating or metabolic disorder comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.
 23. The method of claim 22 wherein said eating disorder is hyperphagia.
 24. The method of claim 22 wherein said metabolic disorder is obesity.
 25. A method of treating a disorder associated with obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 thereof or a pharmaceutically acceptable salt of said compound.
 26. The method of claim 25 wherein the disorder associated with obesity is type II diabetes, insulin resistance, hyperlipidemia or hypertension.
 27. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of claim 1, thereof, or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being a β₃ agonist, a thryomimetic agent, an eating behavior modifying agent or an NPY antagonist; and a pharmaceutically acceptable carrier therefor.
 28. A method of treating an eating disorder which comprises administering to a mammal in need of such treatment an amount of a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being a β₃ agonist, a thryomimetic agent, an eating behavior modifying agent or an NPY antagonist; wherein the amounts of the first and second compounds result in a therapeutic effect.
 29. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, insulin, metformin, acarbose, a thiazolidinedione such as troglitazone or rezulin; a glitazone such as rosaglitazone or pioglitazone; a sulfonylurea, glipazide, glyburide, or chlorpropamide; and a pharmaceutically acceptable carrier therefor.
 30. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier therefor.
 31. A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier. 